Mais conteúdo relacionado Semelhante a Penfigo artigo (20) Penfigo artigo1. Review
Blackwell Publishing Ltd
A review of autoimmune skin diseases in domestic
animals: I – Superficial pemphigus
Thierry Olivry acquisita (collagen VII).1 Similarly, autoantibodies targeting
desmosomal proteins in keratinocytes may result in
Center for Comparative Medicine and Translational Research and blistering diseases of the pemphigus group. This group
Department of Clinical Sciences, College of Veterinary Medicine, encompasses both deep (pemphigus vulgaris: desmoglein-
North Carolina State University, Raleigh, North Carolina, USA
3 ± desmoglein-1; paraneoplastic pemphigus: desmoglein-
Correspondence: Thierry Olivry, Department of Clinical Sciences,
North Carolina State University, College of Veterinary Medicine,
3, plakins) and superficial variants (pemphigus foliaceus:
Research Building, 4700 Hillsborough Street, Raleigh, NC 27606, desmoglein-1; IgA pemphigus, desmocollin-1 and 3).1
USA. E-mail: Thierry_Olivry@ncsu.edu In animals, autoimmune blistering skin diseases were
first recognized 30 years ago, with the seminal description
of pemphigus vulgaris in dogs.2,3 Since then, most animal
Abstract homologues of the human entities have been identified. It
In humans, the pemphigus denomination encompasses is the aim of the forthcoming series of reviews to compile
a group of autoimmune blistering skin diseases with the latest knowledge on autoimmune skin diseases known
intraepidermal separation resulting from cell–cell in domestic animal species. The first monograph of this
detachment by acantholysis. Entities are classified series covers information on the epidemiology, clinical
based on the level of blistering in the epidermis, and signs, treatment outcome, pathology and immunology of
both superficial (pemphigus foliaceus, IgA pemphigus) superficial variants of pemphigus in dogs, cats, horses and
and deep (pemphigus vulgaris, pemphigus vegetans goats. Diseases highlighted herein are pemphigus foliaceus
and paraneoplastic pemphigus) variants are recognized. (PF), pemphigus erythematosus (PE) and the so-called
In domestic animals, subsets of pemphigus have been ‘panepidermal pustular pemphigus’ (PPP).
recognized since the mid-1970s, and the disease classi-
fication resembles that used for human patients. This
article reviews up-to-date knowledge on the epide-
Pemphigus foliaceus
miology, clinical signs, histopathology, immunopathology History
and treatment outcome of superficial pemphigus in The first article describing the existence of PF in dogs was
domestic animals. Detailed information on canine, published in 1977 by Halliwell and Goldschmidt.4 Since
feline, equine and caprine pemphigus foliaceus, canine then, this canine disease has been reported worldwide in
and feline pemphigus erythematosus and canine countless articles, each reporting one or few cases. Only
panepidermal pustular pemphigus is provided. three retrospective studies of large series of subjects (37,
26 and 91 cases) have been published in English.5 –7 The
Accepted 01 August 2006
first report of feline PF was in 1982,8 and there are only
two papers describing more than 10 cases each.6,9 Pem-
phigus foliaceus was recognized in horses in 1981,10 and
three articles report multiple patients.6,11,12 Finally, PF is a
rare autoimmune disease of goats and only scattered
reports exist.13–16
Introduction
Epidermal cells possess structures that are involved Incidence and prevalence
either in cell–cell (desmosomes) or in cell–matrix adhesion Very little epidemiological information on canine PF is
(hemidesmosomes-anchoring fibrils complex). Whenever available, unfortunately. In a veterinary teaching hospital
autoantibodies target proteins in these adhesion struc- (New York State College of Veterinary Medicine at Cornell
tures, intra- or sub-epidermal separation often occurs, and University), PF was diagnosed in 26 of 9750 dogs between
clinical signs of an autoimmune blistering skin disease 1975 and 1984. This proportion results in an estimated
usually develop.1 In the last 30 years, the identification of incidence of PF of approximately three per 1000 canine
antigens targeted by circulating autoantibodies has helped patients referred for skin diseases per year.6 In another
reshape the classification of autoimmune blistering skin institution (Michigan State University College of Veterinary
diseases in humans. Based on clinical signs, histopathology Medicine), PF was the diagnosis made in 1% of surgical
and immunological characteristics, several entities are now skin biopsies read by veterinary pathologists (R. W.
well recognized. For example, the most common diseases Dunstan, personal communication, WSAVA meeting, 1997).
associated with autoantibodies against epidermal basement Finally, in a retrospective study of 84 dogs with auto -
membrane antigens are bullous pemphigoid (target: collagen immune skin diseases, PF was the diagnosis given to
XVII), mucous membrane pemphigoid (laminin-5, collagen 26 subjects, nearly one third of all dogs with autoimmune
XVII, integrin alpha-6 beta-4) and epidermolysis bullosa skin diseases.17
© 2006 The Author. Journal compilation © 2006 European Society of Veterinary Dermatology. 17; 291–305 291
2. Olivry
From data published in one article, the incidence of studies found that PF could affect both very young (less
feline and equine PF could be calculated as five and 10 per than 6 months) and ageing horses of up to 25 years old.6,11,12
1000 patients per 10 years, respectively.6 Pemphigus Finally, there are too few cases of caprine PF for assem-
foliaceus is too rare in goats to estimate its prevalence and bling relevant information on breed, sex and age predis-
incidence. position to disease development.
Signalment Triggering factors for PF
Genetic factors are likely to predispose to the development Environmental factors are suspected to induce flares of
of canine PF. Indeed, data gathered from several studies canine PF. One of such factors may be sunlight exposure.
suggest that PF is more frequently diagnosed in dogs from A decade ago, a book chapter reported a seasonal exacer-
certain breeds. For example, in one group of 37 dogs with bation of the disease with more active flares and requirement
PF, six breeds (bearded collie, Akita, Newfoundland, for higher immunosuppressive drug dosages in warmer
Schipperke, Doberman and Finnish Spitz) exhibited a sig- months, but evidence to support such claims unfortunately
nificant risk to develop the trait compared to the control was not provided.20 In contrast to this assertion, a seasonal
population.5 However, only two of these breeds (Dobermans pattern of PF development was not found in an epidemio-
and Akitas) had more than one representative affected, logical study regrouping 66 dogs with PF.21 More recently,
and both breeds exhibited a high odds ratio (OR) to develop Japanese investigators reported that lesional scores of PF
PF (OR = 29).5 In a second group of 26 dogs,6 Akitas and worsened in the summer in 10/12 dogs studied, while values
dachshunds were the only breeds with more than one improved in the winter.22 Experimentally, irradiation of
individual diagnosed with PF. For dogs reported in this nonlesional skin from a dog with facial-predominant super-
article, we calculated the OR for PF development in Akitas ficial pemphigus with 45–90 kJ m−2 of ultraviolet B (UVB)
to be 3.0 with a large confidence interval (0.7–12.9).6 Using led to epidermal acantholysis after 1 day. In vitro, incuba-
data from the University of Pennsylvania Veterinary Hos- tion of pemphigus serum on UVB-irradiated skin explants
pital, breeds at significant risk of PF development included resulted in more intense intragranular acantholysis than on
Akitas (OR = 38; 95% confidence interval: 13 – 99), English non-irradiated cell cultures.23 The latter findings suggest
cocker spaniels (21; 8–88), chows (12; 4 – 49), shar-peis (8; that additional studies on UV exacerbation of canine
2–30) and collies (4; 2–14). Finally, in a University surgical superficial pemphigus are warranted.
pathology service, three breeds of dogs accounted for one In horses with PF, a higher risk for flares during fall and
third of all cases of PF, and OR for the diagnosis of PF were winter months was reported in one study,12 but a clear
23, 16 and 7 in Akitas, chows and Australian shepherds, seasonal pattern was not observed in the second series of
respectively (R. W. Dunstan, personal communication, cases.11 In two of these 15 horses, however, signs were
WSAVA meeting, 1997). Interestingly, two female Shetland observed to recur each summer.11
sheepdog littermates were reported to develop PF simul- A higher incidence of PF in dogs with allergic skin dis-
taneously at 6 months of age.18 In summary, over the years eases has been mentioned, but evidence supporting such
and in various geographical locations in the USA, chows an association was not given.20 Interestingly, a previous
and Akitas appear to be at high risk to develop PF. This history of flea allergy dermatitis was the most common
common predisposition may not be surprising in light of skin disease reported in dogs later diagnosed with PF in
the recent discovery that these two breeds exhibit closely one study from California.21 This observation must be
related genotypes and are in close phylogenetic linkage.19 taken with caution because of the high prevalence of flea
In the three largest case series of dogs with PF, the allergy dermatitis in that particular geographical location.
male to female sex ratios were 13:24 (0.5), 14:12 (1.2) and In humans, several drugs are suspected to either cause
46:45 (1.0), and these proportions suggest that a sex pre- ‘pharmacological’ acantholysis (i.e. drug-induced pemphigus)
disposition is unlikely to occur in this species.5 –7 In these while others can stimulate disease flares in patients already
reports, the age of onset of canine PF was very variable, predisposed to develop this illness (i.e. drug-triggered
as it ranged from less than one up to 16 years (means: 4.2, pemphigus).24 Cases of drug-related PF have been sus-
6 and 6 years).5 –7 pected in several dogs and rare cats for 20 years.9,25–29 A
A breed predisposition for PF has not been reported recent paper provided information on four additional
definitively in the feline species even though domestic patients.30 In these four dogs, the diagnosis of drug-related
short-haired cats were found to be most commonly affected PF was based on history, clinical signs, histopathology and
with this disease in two case series.6,9 The male to female response to withdrawal of suspected causative drug(s). In
sex ratios were 5:5 and 27:30, suggesting that a sex this paper, however, one subject (case 1) was treated with
predisposition for development of PF in cats also was immunosuppressive doses of prednisolone and azathioprine
unlikely.6,9 In these two studies, the age of onset of feline for 7.5 months, another (case 2) was given high dosages
PF ranged from less than 1 to 9 and 17 years, respectively of prednisolone for 8.5 months, the last patient received
(medians: 5 years).6,9 low dosages of prednisone for 7 months, whereas case 3
In the first study of equine PF, Appaloosas accounted for was not treated with anti-inflammatory medications.30 In
one third of the patients, a proportion five times higher that report therefore two of four patients needed months
than that of the general equine hospital population.6 How- of immunosuppression to maintain remission before all
ever, such breed predisposition was not confirmed in the drugs were discontinued. While one cannot discount the
other two case series.11,12 In none of these three papers authors’ hypothesis that their patients were affected with
was a sex predisposition apparent.6,11,12 While no article drug-related pemphigus, one cannot disprove the contra-
reported an age predilection for disease development, all hypothesis either. Indeed, it is conceivable that the animals
292 © 2006 The Author. Journal compilation © 2006 European Society of Veterinary Dermatology.
3. Superficial pemphigus in domestic animals
mentioned above could have suffered from natural auto-
immune PF that went into prolonged remission after immu-
nosuppression was discontinued, as has been shown
recently in several dogs with PF.31
To evaluate the probability of association between the
administration of a medication and the development of a
particular event, an assessment of likelihood of drug re-
action must be made using ‘adverse drug reaction probability
scales’ such as the one developed years ago by Naranjo
et al.32 When this scale is applied to all previous cases of
putative drug-related pemphigus in dogs and cats25–30 only
low scores interpreted as ‘possible’ probabilities of drug
reaction are obtained. Therefore, at this time, the strength
of evidence supporting drug causation for rare cases of PF
in dogs and cats is weak at best, and further documenta-
Figure 2. Canine facial PF. A 3-year-old Australian shepherd with
tion of canine and feline cases with highly probable drug-
erythema, erosions, scaling and crusting at the time of initial
related PF is critically needed. presentation to the dermatologist (left). Treatment with niacinamide
and tetracycline and intermittent oral prednisone led to minimal
Clinical signs remission with occasional recurrence of signs (right). During disease
Clinical signs of PF appear to be similar across domestic flares, superficial pustules (top right; arrowheads) evolved rapidly into
animal species. In most dogs, lesions initially appear on crusts overlying erosions (bottom right).
the face, principally on the dorsal muzzle, planum nasale,
periocular skin and ears.5,6 In these areas, the pattern usu-
ally is strikingly bilateral and symmetrical (Fig. 1).5 In the
largest case series, lesions were restricted to the face in
15 of 91 dogs (16%) (Fig. 2).7 In rare canine patients, the
dermatosis exhibits a generalized distribution from the
onset, but in most cases, lesions will develop towards
regionalization (Fig. 3) or generalization (Fig. 4) over 3 to 12
months.5,7 In the largest retrospective study, generalized
skin lesions were present in 60/91 dogs (66%), and in
these dogs, crusts were most prevalent on the trunk (58%).7
A remarkable finding of canine PF is the predilection of
lesions for the footpads (Fig. 5).5 Indeed, footpad involve-
Figure 3. Canine PF (same dog as Figure 1). Skin lesions initially
appeared on the face (Figure 1), however, within one week of hair
clipping for cruciate ligament repair surgery and following intense sun
exposure, PF lesions (pustules, erosions and crusts) erupted on the
lateral aspect of the leg where hair had been clipped. Remarkably,
there were no lesions on the medial thigh, an area that had been
clipped also.
ment is seen in one third of dogs with PF,7 and rare canine
patients exhibit lesions restricted solely to this location
(Fig. 5; right).6,7,33–36 Of note is that mucosal lesions are
Figure 1. Canine PF. A 2-year-old chow crossbred dog exhibits crust- only rarely seen in dogs with PF (2/91; 2%).7 Pemphigus
ing and erosions bilaterally and symmetrically distributed on the dorsal foliaceus confined to the claws has been observed in one
muzzle, dorsal nasal planum and periocular areas. dog.37
© 2006 The Author. Journal compilation © 2006 European Society of Veterinary Dermatology. 293
4. Olivry
Figure 4. Canine PF. This 3-year-old English bulldog was affected
with lesions that progressed rapidly from the face to cover most of the
body surface. Inset: details of rapidly drying pustules and crusts from
the lateral thigh. Figure 6. Canine PF. Large, grouped and often coalescing superficial
pustules exhibit a peripheral erythematous halo. Multiple hair shafts
protrude from the roof of the pustule (case material: University of
California Davis).
The nature of skin lesions is comparable in most dogs
with PF: transient pustules evolve rapidly into erosions
and crusts, the latter being the lesions most commonly
seen.5–7 The pustules of PF are usually large and confluent
(Fig. 6), and they often exhibit polycyclic borders. Many
hair shafts can protrude from these pustules, in contrast
to the lesions of bacterial folliculitis where only a single
hair can be seen coming from each pustule.38 On rare
occasions, pustules, erosions and crusts are grouped in
a unique annular, or polycyclic pattern (Fig. 7).5,39 Alopecia
and generalized exfoliative erythroderma are seen
occasionally.5 Pruritus is present in one fourth to one
half of dogs with PF,5 whereas systemic symptoms con-
sisting of anorexia, depression, fever and weight loss are
encountered usually in dogs with widespread erosive
lesions.6
The clinical signs of feline PF are reminiscent of those
seen in dogs with this disease. Pustules are extremely
transient, however, and the phenotype is dominated by Figure 7. Canine PF. Crusts overlie erosions with an erythematous
erosions and yellowish crusts on the face (Fig. 8), ears border in a grouped polycyclic arrangement.
(Fig. 9), and on the feet.6,8,9,40 Pedal lesions, consisting of
suppuration or crusts, can be seen on or around the foot-
pads or ungual folds of claws (Fig. 10).6,8,9,35,40 The pheno- Horses with PF usually are presented with multifocal to
type of feline PF is usually mild and fairly localized, but generalized crusting, scaling and alopecia affecting the
generalized lesions can be seen also.9 The distribution of face, neck, trunk and extremities (Fig. 11).6,11,12 Pustules
lesions of feline PF is usually bilateral and symmetrical.9 are observed rarely, and whenever present, they are
Figure 5. Canine PF. Footpad lesions
of canine PF vary with their chronicity.
Acute lesions (left) consist of pustules
(arrowheads; same dog as in Figure 4),
erosions and crusts. With time, crusts
coalesce (middle) and dry to form fissures
(right).
294 © 2006 The Author. Journal compilation © 2006 European Society of Veterinary Dermatology.
5. Superficial pemphigus in domestic animals
Figure 8. Feline PF. Alopecia, erosions and crusts developed on the
face of a 1.5-year-old Siamese cat during a flare of PF (courtesy of
Dr Barbara Atlee).
Figure 11. Equine PF. A 12-year-old quarterhorse mare exhibits
erosions and crusts in a figurate pattern on the face and neck
(case material from the University of California Davis).
Figure 9. Feline PF. Yellowish crusts are present on the convex (left)
or concave aspects of the pinnae of two cats with PF (left: courtesy
of Dr Barbara Atlee; right: case material from the University of
California Davis).
Figure 12. Canine PF. Aspiration cytology from the content of a
superficial pustule reveals numerous neutrophils, some eosinophils
and scattered isolated or grouped acantholytic keratinocytes
(Diff–Quick).
In goats, pustules, crusts, scales and alopecia predominate
on the face, ventral abdomen, limbs, perineum and tail. In
female animals, lesions may affect the udder and teats.13 –16
Pemphigus foliaceus in animals has been reported in
Figure 10. Feline PF. Crusting can be seen around footpads and
association with systemic diseases such as hypothyroidism,42
claws (left) or on pads themselves (right). leishmaniasis,43 thymoma44 and systemic lupus erythema-
tosus.45 The relationship between PF and these entities
may be coincidental, or it could reflect a systemic disease
transient.6,11,12 Skin lesions may exhibit a unique annular process leading to the induction of immunological imbal-
pattern as in dogs.41 Remarkably, ventral oedema is seen ances and development of anti-keratinocyte autoimmunity.
in many horses with PF.12 Systemic symptoms, such as
depression and lethargy, were noticed in 50% of horses Cytology
with PF in one study6 but a similar observation was not The diagnosis of PF in animals commences with the
made in another retrospective study.11 Lesions of equine demonstration of acantholytic keratinocytes in impression
PF are occasionally painful and /or pruritic.11,12 smears of intact pustules (Fig. 12).5–7 Indeed, isolated to
© 2006 The Author. Journal compilation © 2006 European Society of Veterinary Dermatology. 295
6. Olivry
Figure 13. Canine (left) and feline (right) PF. In these early microscopic lesions, fluid-filled vesico-pustules contain few neutrophils and acantholytic
keratinocytes. The sample on the right was obtained as a shave biopsy from an auricular lesion not existing 2 h before (haematoxylin and eosin).
clustered (e.g. ‘rafts’) free-floating rounded keratinocytes
admixed with nondegenerated neutrophils and rarer eosi-
nophils are seen usually.5–7 Acantholytic keratinocytes
exhibit either microscopic characteristics of normal differ-
entiated spinous or granular layer epithelial cells, or they
present signs of apoptosis with eosinophilic cytoplasm,
condensed chromatin or karyorrhexis. Occasionally, neu-
trophils can be seen in close apposition to detached kerat-
inocytes. The presence of acantholytic keratinocytes and
neutrophils is not specific of PF, however. Similar micro-
scopical findings have been found in canine and equine
cases of pustular dermatophytosis, a PF mimicker in
which Trichophyton fungi invade the stratum corneum and
induce subcorneal acantholytic neutrophilic pustules.46 – 48
Keratinocyte acantholysis has been reported also in dogs Figure 14. Canine PF. Intraepidermal vesico-pustule in the granular
with bacterial skin infections.38 layer of footpad epidermis (haematoxylin and eosin).
Histopathology
In dogs, cats, horses and goats with PF, histological exam-
ination of lesional skin reveals similar findings. Very early
lesions may be vesicles with acantholytic keratinocytes
and scarce neutrophils (Fig. 13). However, these lesions
rapidly evolve into intragranular (Fig. 14) or subcorneal
pustules (Figs 13,14,15) with isolated and /or clustered
acantholytic cells.5,6,38,39 In these lesions, neutrophils pre-
dominate, but variable numbers of eosinophils may be
found.5–7,38,39 Pustules commonly invade the epithelium
and /or the lumen of the follicular infundibulum.5,38 In gen-
eral, the pustules are large and span the length of multiple
follicular units, a finding that differentiates these lesions
from those of bacterial folliculitis.12,38 Similarly, recornifica-
tion, defined as newly reformed stratum corneum at the Figure 15. Canine PF. Intraepidermal to subcorneal neutrophilic
base of neutrophilic pustules, is more suggestive of PF and eosinophilic pustule with single and clustered acantholytic
(Fig. 16) than bacterial folliculitis.38 Microscopic character- keratinocytes. Of interest is the ‘keratin filament ring’ that can be
istics of acantholytic keratinocytes mirror those observed seen in acantholytic or pre-acantholytic keratinocytes (arrowheads)
from the presumed detachment of keratin filaments from
with cytology. Epidermal cells that recently detached from
desmosomes (haematoxylin and eosin).
their neighbours usually appear similar to differentiated
keratinocytes whilst other cells exhibit cytological charac-
teristics of apoptosis.5 Apoptotic keratinocytes are seen apoptosis may reflect the phenomenon of anoikis that fol-
often in the epidermis of dogs with PF,49 and as a result lows the rupture of desmosomal cadherin adhesion during
these apoptotic epidermal cells cannot be taken for bona acantholysis.50 Alternatively, activation of the apoptotic
fide markers of underlying drug reactions. The induction of pathway could be an early consequence of the binding of
296 © 2006 The Author. Journal compilation © 2006 European Society of Veterinary Dermatology.
7. Superficial pemphigus in domestic animals
Figure 16. Feline PF. Large subcorneal neutrophilic acantholytic pustule Figure 17. Canine PF. Direct IF performed on a frozen skin section
with underlying epidermal recornification (haematoxylin and eosin). reveals intercellular epidermal IgG in the stratum spinosum and
granulosum (anticanine IgG fluorescein).
autoantibodies to keratinocytes as shown recently in humans nique was deemed unreliable for the diagnosis of animal
with pemphigus.51 Even though acantholytic keratinoc- pemphigus, as circulating IgG autoantibodies rarely were
ytes can be seen in pyogenic skin bacterial infections38 found in canine, feline or equine sera.6,39 When antikerat-
and pustular dermatophytoses,46– 48 the presence of a inocyte antibodies were detected in canine PF sera, the
high number of free-floating epidermal cells, often seen in titre was usually inferior to 1 : 40.5,6 A recent study pro-
clusters, may be more suggestive of PF than other infec- vided information suggesting that indirect IF results will
tious dermatoses.38 vary according to the substrate utilized for autoantibody
In one study, immunostaining for desmogleins was detection. When normal bovine oesophagus substrate
altered in skin biopsies of dogs with PF compared to those was used, circulating antibodies were detected in 65% of
of normal individuals.52 In canine PF skin, desmoglein affected patients.55 Similarly, indirect IF was positive for all
staining appeared as distinct clumped deposits at the canine PF sera tested on cultured canine keratinocytes.56,57
periphery of keratinocytes and /or dark cytoplasmic stain- When other epidermal substrates were employed, how-
ing of acantholytic cells consistent with internalization of ever, the frequency of detection of circulating autoantibodies
these molecules.52 was usually lower.55 Unfortunately, the skin of the nasal
planum exhibits ‘physiological’ intercellular IgG, rendering
Immunopathology indirect IF testing positive using this substrate and normal
dog sera.55 At North Carolina State University, indirect IF
Direct immunofluorescence testing performed using normal canine footpad revealed
Direct immunofluorescence (IF) or immunoperoxidase antikeratinocyte autoantibody titres superior to 1 : 50 in
have been used to detect antikeratinocyte autoantibodies the serum of 73 of 87 dogs with PF (84%).58 Using this
deposited in vivo in the skin of animals with PF. Skin-fixed substrate, nearly half of canine PF sera tested were
intercellular epidermal IgGs were found in most cats, shown to contain IgG that bound to keratinocytes of both
horses and goats with PF.6,15 Similarly, intercellular epider- stratum spinosum and granulosum, but additional IF
mal IgG autoantibodies were detected in 66 – 80% of patterns also were uncovered.58 These results provided
canine specimens examined (Fig. 17).5,6,17,39,53 One study evidence of immunological heterogeneity of canine PF.58
established that, in some dogs with PF, skin-fixed auto- Using neonatal mouse skin as substrates, canine PF
antibodies belonged to IgG2 and/or IgG4 subclasses.54 In rare serum autoantibodies were detected in 36 of 44 dogs with
instances, intercellular deposits of IgA or IgM and activated PF (82%) (Fig. 18), and they were found to be of either
complement (C3 fraction) were observed.6,39 In one third IgG1 (30/44; 68%) or IgG4 (35/44; 80%) isotypes.59 Similar
of canine specimens, intercellular fluorescence was findings were reported by other investigators.22 In six
restricted to the upper half of the epithelium.5 In some dogs, immunosuppression led to a reduction in clinical
dogs with PF, direct IF testing of skin biopsy specimens scores with serum IgG, IgG1 and IgG4 autoantibody titres
has remained negative, and these results were attributed decreasing in four, one and four patients, respectively.59
to glucocorticoid therapy administered prior to specimen Similarly, serum titres of IgG autoantibodies correlated
collection.6 Unfortunately, intercellular epidermal IgG also with the severity of clinical signs of canine PF in two
can be found in biopsy specimens obtained from dogs with recent reports from the same group.22,60
dermatoses other than PF.6,17 These findings markedly Finally, in one retrospective study, indirect IF testing
reduce the specificity of direct IF testing for the diagnosis revealed circulating antikeratinocyte autoantibodies in 0/9
of canine PF. (0%) and 5/9 (56%) cats and horses with PF, respectively.6
Indirect immunofluorescence Advanced immunological tests
The identification of circulating pemphigus autoantibodies Unfortunately, at this time, studies investigating the nature of
has been performed historically by means of indirect IF autoantigens and pathogenicity of circulating autoantibodies
testing of the animal’s sera. For many years, this tech- of feline, equine and caprine PF have not been reported.
© 2006 The Author. Journal compilation © 2006 European Society of Veterinary Dermatology. 297
8. Olivry
Figure 19. Canine PF. Only rare sera from dogs with PF recognize
canine dsg1 expressed ectopically on the surface of transfected 293T
human kidney cells. These results indicate that dsg1 is only a minor
antigen in dogs with PF (indirect IF, anticanine IgG-fluorescein).66
contrary to previous beliefs, dsg1 appears to be only a
minor autoantigen for canine PF.
A second desmosomal cadherin, desmocollin-1, was
pursued as a tentative autoantigen for PF in dogs. Canine
Figure 18. Canine PF. Serum IgG recognize antigen(s) present on the desmocollin-1 was cloned, sequenced and produced
membrane of superficial epidermal keratinocytes (arrowheads), and ectopically in transiently transfected Chinese hamster
also, in some patients, in the cytoplasm of basal and follicular ovary cells.67 Unfortunately, sera from six dogs with PF did
keratinocytes (arrows, bottom) (indirect IF, neonatal mouse skin not recognize canine desmocollin-1 isolated from trans-
substrate).59
fected cells using immunoprecipitation–immunoblotting.67
Finally, two recent studies provided additional informa-
tion relevant to the localization of putative canine PF anti-
In contrast, the search for canine PF autoantigens has gen(s). In one dog with nondsg1-specific antikeratinocyte
been ongoing for over 15 years. Limited immunoblotting autoantibodies, post-embedding immunoelectron micros-
studies first revealed that serum IgG autoantibodies from copy confirmed the binding of IgG to the extracellular sec-
two of two dogs with PF bound to a 148 kDa antigen tion of desmosomes.65 Finally, whatever the autoantigens
extracted from lip epithelium.61 In another study, autoanti- are, there is evidence for pathogenicity of canine PF IgG.
bodies from eight of 16 dogs were found to bind a 160 kDa Indeed, the intradermal injection into neonatal mouse skin
protein extracted from cultured normal canine keratinoc- of IgG isolated from the serum of three dogs with PF led
ytes.56,62 This 160 kDa antigen was identified also by the to acantholytic blistering below the stratum granulosum
serum of a human patient with PF.56 At first, these 148 and (Fig. 20).68 Remarkably, acantholysis occurred in the
160 kDa antigens were suspected to represent different absence of neutrophil granulocytes in the vesicles.
glycosylation states of canine desmoglein-1 (dsg1), the In summary, at the time of this writing, the identity of
homologue of the major PF antigen in humans. major canine PF antigen(s) remains unknown. The identi-
From the late 1990s to mid-2000s, numerous attempts fication of these antigen(s) may lead to a more precise
were made to determine whether dsg1 was, indeed, the reclassification of superficial pemphigus in dogs based on
main antigen in dogs with PF. The canine dsg1 gene was clinical, histopathological and immunological knowledge.
cloned and sequenced, and it was found to encode a
peptide of 1055 amino acid identical in organization to the Treatment and outcome
human and bovine genes with highest homology existing To date, immune suppression remains the initial therapeu-
in the sequences of the aminoterminal EC1 and EC2 tic intervention of choice for PF in domestic animals. Of
segments.63 The extracellular segment of canine dsg1 note is that all recommendations for immunosuppression
was produced using the baculovirus expression system.64 initially were based on interventions used for treatment of
Remarkably, this recombinant protein was recognized by the human disease, and prospective clinical trials were not
sera from human patients with PF, but it was not identified performed to optimize protocols for animals. As a result,
by IgG from any of the canine PF sera tested.62,65 information in the following paragraphs was collated almost
Recently, human 293T kidney cells were transfected to exclusively from retrospective case series. Historically,
express ectopically membrane-bound canine dsg1. Indirect standard-of-care treatment of canine PF relied on the
IF staining established that only five of 83 canine PF sera induction of immunosuppression with oral glucocorticoids,
(6%) recognized canine dsg1-transfected human cells such as prednisone or prednisolone, at daily dosages var-
(Fig. 19).66 When present, antidsg1 IgG autoantibodies ying from 2 to 6.6 mg kg−1 divided in one or two adminis-
were found to target calcium and glycosylation-dependent trations.5–7,69 If lesions decreased in extent and severity
epitopes.66 In summary, at the time of this writing and in with this regimen, then the dose and /or administration
298 © 2006 The Author. Journal compilation © 2006 European Society of Veterinary Dermatology.
9. Superficial pemphigus in domestic animals
More recently, 43 dogs with PF were seen at the Uni-
versity of Pennsylvania between 1994 and 2000.73 Of these
patients, only 17 of 43 subjects (40%) were still alive at the
end of the study period. Most dogs died during the first
year of treatment. Of the dogs that died, 18 of 26 (69%)
were euthanized because of lack of response of lesions to
therapy, poor quality of life or adverse effects of treat-
ment.73 Interestingly, the addition of antibiotics during the
induction of immunosuppression was associated with a
significant improvement in survival rate in this cohort of
patients.73
In contrast to such results that suggest a poor outcome
following ‘standard-of-care’ therapy with combined oral
immunosuppression, Rosenkrantz reported a 71% survival
Figure 20. Canine PF. The intradermal injection of IgG from dogs with rate after one year in 31 dogs with PF with only four dogs
PF into neonatal mouse skin results in subgranular blister formation, euthanized because of poor response to therapy or treat-
thereby confirming the pathogenicity of serum autoantibodies ment discontinuation with subsequent relapses.69 Similarly,
(haematoxylin and eosin).68
the latest series of 91 dogs with PF reported by Mueller
and colleagues provided additional data on favourable
treatment outcome.7 Of 88 dogs treated for PF, 46 under-
frequency of glucocorticoids was reduced with the goal of went complete remission (52%), 31 (35%) achieved
rapidly achieving alternate day intake.5,69 In many canine partial remission of lesions, and only 11 (13%) were euth-
patients, however, glucocorticoid therapy alone appears anized.7 Reasons for euthanasia included lack of response
incapable in halting or slowing the progression of skin to treatment (4/11; 36%), unacceptable side-effects of
lesions.5 In these cases, cytotoxic drugs are usually medications used (2/11; 18%) and unrelated or unknown
added.5,6,69 Azathioprine (2–2.5 mg kg−1, orally, once daily), causes.7 Complete remission was achieved with oral glu-
cyclophosphamide (25 mg m−2, orally, once daily) or chlo- cocorticoids in 15 of 39 dogs (38%) within 1.5–12 months
rambucil (0.2 mg kg−1 every 24 – 48 h) have been proposed of treatment initiation (average: 7 months), and this occurred
as adjunct cytotoxic drugs.5,6,69 Alternatively, immune modu- with a glucocorticoid–azathioprine combination in 18 of 33
lation with injectable aurothioglucose (1 mg kg−1 week−1) dogs (55%) within 2–29 months (average: 12 months) of
was used two decades ago to treat dogs with unacceptable starting therapy. Therefore, the addition of azathioprine did
side-effects of immune suppressive medications.5,6 not lead to a significant difference in the time needed to
Finally, rare dogs with PF exhibit lesions that respond to achieve remission compared to the use of glucocorticoids
tetracycline and niacinamide (250–500 mg of each, three alone.7 In five dogs, however, the sole administration of
times daily).7,70 prednisolone was unsuccessful, and the addition of azathi-
In recent years, two small prospective open clinical trials oprine led to complete lesion remission.7 Remarkably,
explored the efficacy of novel drugs for treatment of dogs adverse drug events occurred significantly more often with
with PF. In a 16-week pilot study, eight subjects were prednisolone–azathioprine combination than glucocorticoids
treated with mycophenolate mofetil at 20 – 40 mg kg−1 per alone. These observations suggest that a prospective
day, divided in three daily doses.71 In three dogs, a reduc- study must be undertaken to determine whether or not
tion of lesional area and /or severity were seen. Four subjects the addition of azathioprine offers any benefit to glucocor-
did not complete the study and two were euthanized. ticoid monotherapy in dogs with PF.
Additionally, all dogs required concurrent glucocorticoid In this series of dogs with PF, there were no significant
therapy to control the severity of skin lesions.71 As a result differences in either rate of complete remission or death
of high cost and limited proven benefit, there is currently between dogs with facial localized vs. generalized lesions,
insufficient evidence for recommending this drug for treat- dogs treated with prednisolone alone vs. prednisolone and
ment of canine PF. azathioprine combination, or dogs treated with immuno-
Recently, a small pilot study evaluating the efficacy of suppression with or without antibiotics.7 In summary, the
oral cyclosporin (5 –10 mg kg−1 once daily) in five dogs with review of treatment outcome in this cohort of dogs with
PF was reported.72 Four dogs did not complete the trial PF suggests that the benefit of azathioprine addition to
because of perceived lack of efficacy. In one dog, there was oral glucocorticoid regimens must be weighed carefully
a transient reduction in lesional scores.72 Future studies against the cost of treatment monitoring and additional
should evaluate whether this drug could be used as a risk to patients.
glucocorticoid-sparing agent, or whether higher dosages Finally, the persistence of long-term remission of canine
are needed to induce lesion remission. PF after discontinuation of immunomodulating therapy
The treatment outcome of canine PF appears to be has been reported in 7–22% of dogs with PF.31 Similar
variable, presumably because of variations in treatment results were obtained in two of 88 dogs (2%) in the most
protocols and /or disease subtypes. In articles describing recent case series. 7
cases seen in the 1970s and 1980s, 18 of 34 (53%)5 and In cats with PF, glucocorticoid monotherapy usually is
23 of 26 (88%) dogs with PF6 were reported to have been effective for achieving clinical remission. Historically, the
‘managed successfully’ with the interventions mentioned oral glucocorticoids of choice have been prednisone (4–
above. 5 mg kg−1 daily) and triamcinolone (0.6–2 mg kg−1 daily).9
© 2006 The Author. Journal compilation © 2006 European Society of Veterinary Dermatology. 299
10. Olivry
Recent pharmacological data, however, have shown that human cicatricial pemphigoid within the spectrum of
oral prednisone is not very well absorbed and /or con- ‘mucous membrane pemphigoid’.80 Whether feline, equine
verted into prednisolone in cats, therefore suggesting that and caprine PF are immunologically heterogeneous cur-
oral prednisolone is a better choice than prednisone in this rently remains unknown.
species.74 In cats whose PF lesions fail to respond to glu- As a result, and until further studies allow a refinement
cocorticoids, chlorambucil (0.2 mg kg−1, orally, once daily) in the nosology of this syndrome, we propose that the
is the cytotoxic drug most commonly used.9,75 Even though diagnosis of PF be based principally on clinico-pathological
azathioprine has been used successfully to treat cats with grounds. Therefore, it is suggested that, at this time, the
PF40 this drug is no longer used widely as it is known to diagnosis of PF be given to animals that suffer from a skin
cause profound neutropenia and thrombocytopenia in disease satisfying ALL three criteria below:
feline patients.76 This abnormal sensitivity to azathioprine
may be due to their recently discovered lower activity of 1 Clinical examination: pustules rapidly evolving in
thiopurine methyltransferase, an enzyme that metabolizes shallow erosions and crusts with predominance to
azathioprine and whose deficiency can cause severe the face and feet
myelosuppression.77,78 Sometimes, lesions of feline PF 2 Histopathology: superficial epidermal or follicular
respond to aurothioglucose.6 pustules rich in neutrophils and often-clustered
In one study, complete remission of PF lesions occurred acantholytic keratinocytes
in 15 of 15 cats (100%) using triamcinolone alone, in eight 3 Differential diagnoses: rule out of other acantholytic
of 13 (62%) using prednisone alone, and in nine of 11 neutrophilic pustular diseases, especially exfoliatin-
(82%) using a prednisone/chlorambucil combination.9 In associated staphylococcal pyodermas and pustular
that series of cases, cats receiving triamcinolone exhibited dermatophytosis due to corneophilic dermatophytes.
a higher rate of complete remission and a lower rate of
adverse drug events than those receiving a prednisone/
chlorambucil combination.9 Only four of 30 cats (13%) for Pemphigus erythematosus
which long-term treatment outcome was known were In humans, PE is a controversial clinically heterogeneous
euthanized because of their disease or to treatment com- entity that has been historically linked to both discoid
plications.9 In an older series of 10 cats with PF, treatment lupus erythematosus (DLE) and superficial pemphigus.81
with prednisolone was reported to be effective in six subjects Supporting the current concept that human PE in fact rep-
(60%) and with aurothioglucose in four patients (40%).6 resents a variant of PF, immunological investigations have
Similarly to dogs and cats with this disease, lesions of confirmed the identity of the main human PE autoantigen
PF can be treated successfully in horses and goats with as dsg1, the major PF antigen.82,83 Additionally, serum
either prednisolone or dexamethasone alone or in combi- autoantibodies targeting the basement membrane zone
nation with aurothioglucose.6,12,15 As is seen in cats, pred- antigens bullous pemphigoid antigen 1 (230 kDa) and peri-
nisone may be of limited efficacy in horses due to its poor plakin (190 kDa) have been identified in rare patients.83
absorption and/or biotransformation into prednisolone.79 The first mention of the existence of PE in animals was
In one of the retrospective studies, five of 13 horses in a general review article of immunological skin diseases
(38%) were euthanized for either lack of response of by Scott in 1978.84 Two years later, the same author included
lesions to treatment or development of steroid-induced previously reported cases in an article describing clinical,
acute laminitis.12 Four of 11 horses (36%) remained in histopathological and immunological characteristics of
remission for more than one year after immunosuppres- four dogs and one cat with PE.85 In June 2006, the search
sion lasting from three to 12 months was discontinued.12 of several reference databases identified – in addition to
In the second study, follow-up information was reported the original princeps descriptions – only one case series of
for seven of 15 horses.11 Only one subject was euthanized nine dogs6 and scattered case reports of canine39,86– 90
due to financial constraints, while the other horses achieved and feline PE.91
remission with prednisone, prednisolone or aurothioglu- In the largest case series, PE was reported to be the
cose.11 In one horse, long-term remission was maintained third most common form of pemphigus seen at Cornell
in the absence of treatment.11 Of note is that none of the University Veterinary Teaching Hospital, yet patients with
three published case series provided information substan- PE only accounted for less than one of 1000 dogs and cats
tiating the previously held belief that equine PF is of better presented with skin diseases over 10 years.6 Unfortunately,
prognosis in young horses than in old subjects. due to the scarcity of information on canine and feline PE,
detailed information on any breed, age and sex predispo-
Conclusions: diagnosing pemphigus foliaceus in sition for this disease cannot be provided.
domestic animals Clinically, dogs and cats with PE are reported to present
In summary, at the time of this writing (June 2006), it is with pustules erosions and crusts localized to the face
apparent that canine PF appears to be clinically, histologi- and pinnae along with depigmentation, erythema and
cally and immunologically heterogeneous with only rare erosion/ulceration of the nasal planum and dorsal muzzle
patients having autoantibodies targeting dsg1, the canine (Fig. 21).6,39,85–91 Only rare patients exhibit nonfacial lesions.6
homologue of the major human PF antigen. It is likely Microscopic examination of skin biopsies of dogs and cats
therefore that the entity currently called ‘canine PF’ may with PE reveals intragranular to subcorneal neutrophilic
not be a single disease, but a clinicopathological syndrome and eosinophilic acantholytic pustules suggestive of PF
regrouping several immunological variants. In many ways, along with a lichenoid interface dermatitis that resembles
this situation is similar to the recent reclassification of that of DLE.6,39,85–91
300 © 2006 The Author. Journal compilation © 2006 European Society of Veterinary Dermatology.
11. Superficial pemphigus in domestic animals
Figure 21. canine ‘PE’. A 2-year-old collie
presented with a pustular, erosive and
crusting dermatosis bilaterally and
symmetrically distributed to the face (left)
and ears. Additionally, there were
depigmenting atrophic scars, erosions and
crusts on the dorsal nasal planum (right,
top) as well as depigmentation, scarring
and deep erosions/ulcers on the ventral
nares (right, middle and bottom).
Histological and immunological
characteristics resembled those previously
reported for canine PE.
On direct IF examination, skin biopsy specimens of 3 Superficial acantholytic epidermal pustules are seen
canine and feline PE uniquely exhibit both intercellular in both canine PF and PE, while the presence of a
epidermal pemphigus-like and basement membrane lichenoid ± interface dermatitis in the latter may only
lupus-like depositions of immunoglobulins with or without reflect the nasal/paranasal location of skin biopsies in
activated complement.6 Of note is that not all dogs with dogs with PE. Indeed, dogs with various nasal derm-
PE will have this basement membrane immunoreagent atoses often exhibit a band-like diffuse superficial
deposition.6,85 Indirect IF performed with canine and feline plasmacytic to lymphoplasmacytic dermatitis with or
PE sera has remained negative for all patients tested.6,85 without basal cell damage.92
In contrast, low serum titres of antinuclear antibodies 4 The observation of immunoglobulins and complement
(1 : 10 –1 : 40) have been identified in approximately half at the basement membrane zone by direct IF is not
of sera from dogs with PE.6,85 specific for lupus, as it is seen also in canine PF and
The treatment outcome of canine and feline PE is numerous other immune-mediated skin diseases.53,93
reported to be good, with lesions responding to immuno- Moreover, serum antibasement membrane autoanti-
suppressive regimens used to treat patients with PF.6 In bodies can be detected in some dogs with PF.58
one of two dogs with PE, the administration of a tetracycline 5 The presence of low serum titres of antinuclear anti-
and niacinamide regimen resulted in a partial resolution of bodies in dogs with PE is not unique to this entity
clinical signs.70 The use of sun avoidance and sunscreens because of the recent observation that nearly 30% of
has been advocated.6 Finally, topical treatment with 0.1% dogs with various phenotypes of PF also exhibit low
tacrolimus ointment was reported to be of benefit, as an titres of serum IgG targeting nuclear antigens.58
adjunct medication, in two dogs with PE.89 6 Finally, PE cannot be individualized from PF on the
In summary, the rare descriptions of canine and feline basis of differing treatment outcomes as a favourable
PE published since 1980 have implied that this disease response to treatment is seen both in dogs with PE and
represented an unusual facial-predominant dermatosis with in canine patients with localized or generalized PF.7
clinical, histopathological and immunopathological charac-
teristics of both PF and DLE. As a result, the current dogma In summary, at this time, there is insufficient evidence
is that PE might be a crossover between these two entities. supporting that canine PE is markedly different from local-
This concept must be considered controversial, how- ized facial PF either clinically, histologically, immunologi-
ever. Indeed, the rationale for previous individualization cally or prognostically. Additional studies are needed to
of canine PE as an entity distinct from PF needs to be re- determine whether there would be any value – for either
examined in light of recent knowledge suggesting that patients or clinicians – in individualizing canine PE as a
both diseases exhibit very similar characteristics: separate entity, whether it should be reclassified as a
localized variant of PF, or whether it is a genuine crossover
1 The predominance of skin lesions to the face is not between PF and DLE or other entities. Similarly, there is
unique to PE, as facial lesions are identified also in not enough information on feline PE and PF to permit an
most dogs with PF, and they are restricted to this area accurate separation between these two diseases.
in 16% of canine patients with this disease.7
2 Photosensitivity is not specific for canine PE, as pre-
liminary evidence suggests that this phenomenon Panepidermal pustular pemphigus
exists also for canine PF (see discussion in the PF In 1994, Wurm, Mattise and Dunstan proposed the crea-
section). tion of a new entity named ‘canine panepidermal pustular
© 2006 The Author. Journal compilation © 2006 European Society of Veterinary Dermatology. 301
12. Olivry
pemphigus’ to regroup cases previously diagnosed as years of continuous technical support by Stan Dunston
pemphigus vegetans and PE.94 The main criteria for diag- also is acknowledged.
nosing canine PPP were the demonstration of neutrophil-
rich and eosinophil-rich acantholytic pustules at all layers References
of the epidermis and the suprabasal infundibular outer root
1. Fassihi H, Wong T, Wessagowit V et al. Target proteins in inherited
sheath epithelium.94 A considerable morphologic overlap and acquired blistering skin disorders. Clinical and Experimental
between PPP and PF in dogs was noted to exist, but the Dermatology 2006; 31: 252–9.
main difference between these two entities was the 2. Stannard AA, Gribble DH, Baker BB. A mucocutaneous disease in
observation of pustules in the granular and upper spinous the dog resembling pemphigus vulgaris in man. Journal of the
layers in PF and the occurrence of these lesions through- American Veterinary Medical Association 1975; 166: 575–82.
out the epidermis in PPP.94 3. Hurvitz AI, Feldman E. A disease in dogs resembling human pem-
phigus vulgaris: case reports. Journal of the American Veterinary
The rationale for creating an entity solely based on
Medical Association 1975; 166: 585–90.
histological grounds is subject to controversy. Indeed, as 4. Halliwell REW, Goldschmidt MH. Pemphigus foliaceus in the
noted above, there is current evidence of clinical, his- canine: a case report and discussion. Journal of the American Ani-
topathological and immunological heterogeneity among mal Hospital Association 1977; 13: 431–6.
dogs diagnosed with PF, and the individualization of distinct 5. Ihrke PJ, Stannard AA, Ardans AA et al. Pemphigus foliaceus in
subsets of canine pemphigus must await the determina- dogs: a review of 37 cases. Journal of the American Veterinary
Medical Association 1985; 186: 59–66.
tion whether the identification of the various autoantigens
6. Scott DW, Walton DK, Slater MR et al. Immune-mediated derma-
targeted provides a rationale for a revision of disease clas- toses in domestic animals: ten years after – Part I. Compendium
sification. Indeed, the observation of microscopic lesions on Continuing Education for the Practicing Veterinarian 1987; 9:
arising at different epithelial depth simply could be due to 424–35.
variability in distribution of antigens targeted by autoanti- 7. Mueller RS, Krebs I, Power HT et al. Pemphigus foliaceus in 91
bodies at different body locations. This concept is best dogs. Journal of the American Animal Hospital Association 2006;
illustrated by the recent discovery that, for example, dsg1 42: 189–96.
8. Manning TO, Scott DW, Smith CA et al. Pemphigus diseases in
can be detected on keratinocytes of all epidermal layers in
the feline: seven case reports and discussion. Journal of the
the dorsal muzzle, pinna and footpads of dogs.95 In contrast, American Animal Hospital Association 1982; 18: 433–43.
dsg1 is visible only in the upper layers of canine shoulder, 9. Preziosi DE, Goldschmidt MH, Greek JS et al. Feline pemphigus
groin or abdomen epidermis.95 Therefore, dogs with antidsg1 foliaceus: a retrospective analysis of 57 cases. Veterinary Derma-
associated pemphigus would be more likely to exhibit tology 2003; 14: 313–21.
superficial lesions on the abdomen and groin and more 10. Johnson ME, Scott DW, Manning TO. A case of pemphigus
‘panepidermal’ lesions on the muzzle, ears and footpads. foliaceus in the horse. Equine Practice 1981; 3: 40–5.
11. Zabel S, Mueller RS, Fieseler KV et al. Review of 15 cases of
In summary, at the time of this writing, there is little
pemphigus foliaceus in horses and a survey of the literature.
evidence supporting the separation of canine PPP from the Veterinary Record 2005; 157: 505–9.
main superficial pemphigus group (e.g. PF). Further studies 12. Vandenabeele SIJ, White SD, Affolter VK et al. Pemphigus foliaceus
are needed to determine whether clinical, treatment in the horse: a retrospective study of 20 cases. Veterinary Derma-
outcome and immunological information warrants the tology 2004; 15: 381–8.
individualization of PPP as a bona fide entity. 13. Scott DW, Smith MC, Smith CA. Pemphigus foliaceus in a goat.
Agri Practice 1984; 5: 38–45.
14. Jackson PGG, Lloyd S, Jeffries AR. Pemphigus foliaceus in a
Conclusions goat. Veterinary Record 1984; 114: 479.
15. Valdez RA, Gelberg HB, Morin DE et al. Use of corticosteroids and
The last decades have seen the discovery of canine, feline, aurothioglucose in a pygmy goat with pemphigus foliaceus. Journal
equine and caprine homologues of superficial pemphigus of the American Veterinary Medical Association 1995; 207: 761–5.
in humans. The 1980s and early 1990s saw the separation 16. Pappalardo E, Abramo F, Noli C. Pemphigus foliaceus in a goat.
of several subtypes of pemphigus (PF, PE and PPP) Veterinary Dermatology 2002; 13: 331–6.
17. Werner LL, Brown KA, Halliwell REW. Diagnosis of autoimmune
because of minor differences in gross and microscopic
skin disease in the dog: correlation between histopathologic,
lesions. However, the recent observation of clinical, histo- direct immunofluorescent and clinical findings. Veterinary Immu-
logical or immunological overlap between these three nology and Immunopathology 1983; 5: 47–64.
entities and the discovery of marked heterogeneity among 18. Noxon JO, Myers RK. Pemphigus foliaceus in two Shetland
dogs with PF suggests that, until further investigations sheepdog littermates. Journal of the American Veterinary Medical
have characterized the major autoantigens in this group of Association 1989; 194: 545–6.
diseases, there is not enough evidence to warrant individ- 19. Parker HG, Kim LV, Sutter NB et al. Genetic structure of the pure-
bred domestic dog. Science 2004; 304: 1160–4.
ualizing subsets within the superficial pemphigus group in
20. Rosenkrantz WS. Pemphigus foliaceus. In: Griffin CE, Kwochka
animals. The terminology of ‘PF’ remains most appropriate KW, MacDonald JM, eds. Current Veterinary Dermatology – the
at this time, keeping in mind that this denomination might Science and Art of Therapy. St Louis, MO: Mosby Year Book,
represent a syndrome rather than a homogeneous entity. 1993, 141–8.
21. Pascal A, Shiebert J, Ihrke P. Seasonality and environmental risk
factors for pemphigus foliaceus in animals: a retrospective study
Acknowledgements and funding of 83 cases presented to the Veterinary Medical Teaching Hospital,
University of California Davis from 1976 and 1994 (abstract). Pro-
The author is grateful to Drs Gregg Dean, Luis Diaz, Toshiroh ceedings of the American Academy of Veterinary Dermatology
Iwasaki, Eliane Mueller, Koji Nishifuji, Maja Suter, Simon and American College.of Veterinary Dermatology Annual Meeting.
Warren and Zhi Liu for their past and current collaborations Santa Fe, NM: American Academy of Veterinary Dermatology,
in the field of canine pemphigus foliaceus research. Twelve 1995: 24–5.
302 © 2006 The Author. Journal compilation © 2006 European Society of Veterinary Dermatology.
13. Superficial pemphigus in domestic animals
22. Iwasaki T, Yamakita-Yoshida K. Time course of autoantibodies and association with systemic lupus erythematosus, and subsequent
clinical signs in canine pemphigus foliaceus (Abstract). Proceed- lymphoma in a cocker spaniel. Journal of Small Animal Practice
ings of the American Academy of Veterinary Dermatology and 2000; 41: 266–70.
American College of Veterinary Dermatology Annual Meeting. 46. Scott DW. Marked acantholysis associated with dermatophytosis
Monterey, CA: American Academy of Veterinary Dermatology. due to Trichophyton equinum in 2 horses. Veterinary Dermatology
2003, 240. 1994; 5: 105–10.
23. Iwasaki T, Maeda Y. The effect of ultraviolet (UV) on the severity 47. Parker WM, Yager JA. Trichophyton dermatophytosis – A disease
of canine pemphigus erythematosus (Abstract). Proceedings of easily confused with pemphigus erythematosus. Canadian Veter-
the American Academy of Veterinary Dermatology and American inary Journal – Revue Veterinaire Canadienne 1997; 38: 502–5.
College of Veterinary Dermatology Annual Meeting Annual Meet- 48. Poisson L, Mueller RS, Olivry T. Dermatophytose pustuleuse
ing. Nashville, TN: American Academy of Veterinary Dermatology. cornéophilique canine évoquant un pemphigus foliacé [Canine
1997: 86. pustular dermatophytosis of the stratum corneum mimicking
24. Wolf R, Tamir A, Brenner S. Drug-induced versus drug-triggered pemphigus foliaceus]. Pratique Medicale et Chirurgicale de L Ani-
pemphigus. Dermatologica 1991; 182: 207–10. mal de Compagnie 1998; 33: 229–34.
25. McEwan NA, McNeil PE, Kirkham D et al. Drug eruption in a cat 49. Noli C, von Tscharner C, Suter MM. Apoptosis in selected skin
resembling pemphigus foliaceus. Journal of Small Animal Practice diseases. Veterinary Dermatology 1998; 9: 221–9.
1987, 28. 50. Ruoslahti E, Reed JC. Anchorage dependence, integrins and
26. Mason KV, Day MJ. A pemphigus foliaceus-like eruption associated apoptosis. Cell 1994; 7: 477–8.
with the use of ampicillin in a cat. Australian Veterinary Journal 51. Frusic-Zlotkin M, Pergamentz R, Michel B et al. The interaction of
1987; 64: 223–4. pemphigus autoimmunoglobulins with epidermal cells: activation
27. Medleau L, Shanley KJ, Rakich PM et al.Trimethoprim–sulfonamide- of the Fas apoptotic pathway and the use of caspase activity for
associated drug eruptions in dogs. Journal of the American Animal pathogenicity tests of pemphigus patients. Annals of the New
Hospital Association 1990; 26: 305–11. York Academy of Sciences 2005; 1050: 371–9.
28. Prélaud P, Mialot M, Kupfer B. Accident cutané médicamenteux 52. Steeves EB, Chelack BJ, Clark EG et al. Altered immunohisto-
évoquant un pemphigus foliacé chez un chat. Point Vétérinaire chemical staining for desmoglein in skin biopsies in canine pem-
1991; 23: 313–8. phigus foliaceus. Journal of Veterinary Diagnostic Investigation
29. Noli C, Koeman JP, Willemse T. A retrospective evaluation of 2002; 14: 53–6.
adverse reactions to trimethoprim-sulfonamide combinations in 53. Day MJ, Hanlon L, Powell LM. Immune-mediated skin disease in
dogs and cats. Veterinary Quarterly 1995; 17: 123–8. the dog and cat. Journal of Comparative Pathology 1993; 109:
30. White SD, Carlotti DN, Pin D et al. Putative drug-related pemphi- 395–407.
gus foliaceus in four dogs. Veterinary Dermatology 2002; 13: 54. Day MJ, Mazza G. Tissue immunoglobulin G subclasses observed
195–202. in immune-mediated dermatopathy, deep pyoderma and hyper-
31. Olivry T, Bergvall KE, Atlee BA. Prolonged remission after immu- sensitivity dermatitis in dogs. Research in Veterinary Science
nosuppressive therapy in six dogs with pemphigus foliaceus. 1995; 58: 82–9.
Veterinary Dermatology 2004; 15: 245–52. 55. Iwasaki T, Shimizu M, Obata H et al. Effect of substrate on indi-
32. Naranjo CA, Busto U, Sellers EM et al. A method for estimating rect immunofluorescence test for canine pemphigus foliaceus.
the probability of adverse drug reactions. Clinical Pharmacology Veterinary Pathology 1996; 33: 332–6.
and Therapeutics 1981; 30: 239–45. 56. Iwasaki T, Shimizu M, Obata H et al. Detection of canine pemphigus
33. August JR, Chickering WR. Pemphigus foliaceus causing lame- foliaceus autoantigen by immunoblotting. Veterinary Immunology
ness in four dogs. Compendium on Continuing Education for the and Immunopathology 1997; 59: 1–10.
Practicing Veterinarian 1985; 7: 894–902. 57. Honda R, Nishifuji K, Olivry T et al. Detection of circulating autoan-
34. Ihrke PJ, Stannard AA, Ardans AA et al. Pemphigus foliaceus of tibodies using living keratinocyte staining on MCA-B1 method in
the footpads in three dogs. Journal of the American Veterinary dogs with pemphigus foliaceus. Research in Veterinary Science
Medical Association 1985; 186: 67–9. 2004; 77: 105–13.
35. Bensignor E, Carlotti D-N. A propos de quatre cas de pemphigus 58. Lennon EM, Dunston SM, Olivry T. Immunological heterogeneity
foliacé avec atteinte exclusive des coussinets. Pratique Médicale of canine pemphigus foliaceus: I – variability of indirect immun-
et Chirurgicale de L’animal de Compagnie 1997; 32: 481–90. ofluorescence patterns (Abstract). Veterinary Dermatology 2006;
36. High M. An interesting case of pemphigus foliaceus in a dog. 17: 216.
Canadian Veterinary Journal 1999; 40: 127–8. 59. Hogan RM, Dunston SM, Alhaidari Z et al. Immunofluorescent
37. Guaguere E, Degorce-Rubiales F. Pemphigus foliaceus confined determination of the isotype of serum anti-keratinocyte autoanti-
to the nails in a Hungarian short-haired pointer (Abstract). Veteri- bodies in dogs with pemphigus foliaceus (Abstract). Veterinary
nary Dermatology 2004; 15 (Suppl. 1): 56. Dermatology 2002; 13: 228.
38. Kuhl KA, Shofer FS, Goldschmidt MH. Comparative histopatho- 60. Nishifuji K, Yoshida-Yamakita K, Iwasaki T. A canine pemphigus
logy of pemphigus foliaceus and superficial folliculitis in the dog. foliaceus case showing parallel relationship of disease activity
Veterinary Pathology 1994; 31: 19–27. and titer of serum anti-keratinocyte cell surface antibodies.
39. Olivry T. Les dermatoses auto-immunes du chien et du chat (Dr. Journal of Veterinary Medical Science 2005; 67: 943–5.
Vet. Thesis). Toulouse, France: Université Paul-Sabatier, 1986. 61. Suter MM, Ziegra CJ, Cayatte SM et al. Identification of canine
40. Caciolo PL, Nesbitt GH, Hurvitz AI. Pemphigus foliaceus in eight pemphigus antigens. In: Ihrke PJ, Mason IS, White, SD, eds.
cats and results of induction therapy using azathioprine. Journal Advances in Veterinary Dermatology, Vol. 3. Oxford: Pergamon
of the American Animal Hospital Association 1984; 20: 572–7. Press, 1993: 367–80.
41. Scott DW. Autoimmune skin diseases in the horse. Equine Practice 62. Iwasaki T, Olivry T. Spontaneous canine model of pemphigus
1989; 11: 20–32. foliaceus. In: Chan LS, ed. Animal Models of Human Inflammatory
42. Guaguère E, Magnol J-P, Olivry T. Cas clinique: pemphigus Skin Diseases. Boca Raton, FL: CRC Press, 2004: 309–19.
foliaceus et hypothyroïdie chez un briard. Point Vétérinaire 1985; 63. Müller E, Caldelari R, Levine R et al. Cloning of canine Dsg1 and
17: 155. evidence for alternative polyadenylation. Journal of Investigative
43. Ginel PJ, Mozos E, Fernández A et al. Canine pemphigus Dermatology 2000; 114: 1211–3.
foliaceus associated with leishmaniasis. Veterinary Record 1993; 64. Nishifuji K, Amagai M, Nishikawa T et al. Production of recom-
133: 526–7. binant extracellular domains of canine desmoglein 1 (Dsg1) by
44. Day MJ. Review of thymic pathology in 30 cats and 36 dogs. baculovirus expression. Veterinary Immunology and Immunopa-
Journal of Small Animal Practice 1997; 38: 393–403. thology 2003; 95: 177–82.
45. Foster AP, Sturgess CP, Gould DJ et al. Pemphigus foliaceus in 65. Yabuzoe A, Nishifuji K, shimizu A et al. Ultrastructural localization
© 2006 The Author. Journal compilation © 2006 European Society of Veterinary Dermatology. 303
14. Olivry
of binding site of serum antibodies in pemphigus foliaceus criteria, pathogenic factors, medical treatment and prognostic
by post-embedding immunoelectron microscopy in one dog indicators. Archives of Dermatology 2002; 138: 370–9.
(Abstract). Veterinary Dermatology 2006; 17: 220. 81. Bharti R, Lazova R. Pemphigus erythematosus (last update:
66. Olivry T, LaVoy A, Dunston SM et al. Desmoglein-1 is a minor 1 June 2005). http://www.emedicine.com/DERM/topic317.htm
autoantigen in dogs with pemphigus foliaceus. Veterinary (last accessed: May 17, 2006).
Immunology and Immunopathology 2006; 110: 245–55. 82. Gomi H, Kawada A, Amagai M et al. Pemphigus erythematosus:
67. Aoki-Ota M, Ota T, Kadoya M et al. Autoantibodies agains detection of anti-desmoglein-1 antibodies by ELISA. Dermatology
extracellular domains of desmocollin 1 are not involved in canine 1999; 199: 188–9.
pemphigus foliaceus (Abstract). Veterinary Dermatology 2004; 15 83. Karlhofer FM, Hashimoto T, Slupetzky K et al. 230-kDa and 190-
(Suppl. 1): 26. kDa proteins in addition to desmoglein 1 as immunological targets
68. Olivry T, Dunston SM, Warren SJ et al. Canine pemphigus auto- in a subset of pemphigus foliaceus with a combined cell-surface and
antibodies are pathogenic in neonatal mice (Abstract). Journal of basement membrane zone immune staining pattern. Experimental
Investigative Dermatology 2002; 119: 301. Dermatology 2003; 12: 646–54.
69. Rosenkrantz WS. Pemphigus: current therapy. Veterinary Derma- 84. Scott DW. Immunologic skin disorders in the dog and cat. Veterinary
tology 2004; 15: 90–8. Clinics of North America – Small Animal Practice 1978; 8: 641–64.
70. White SD, Rosychuk RAW, Reinke SI et al. Use of tetracycline 85. Scott DW, Miller WH, Lewis RM et al. Pemphigus erythematosus
and niacinamide for treatment of autoimmune skin disease in in the dog and the cat. Journal of the American Animal Hospital
31 dogs. Journal of the American Veterinary Medical Association Association 1980; 16: 815–23.
1992; 200. 86. Kaufman GM, Blakemore JC. Facial dermatitis in a dog. Compen-
71. Byrne KP, Morris DO. Study to determine the usefulness of dium on Continuing Education for the Practicing Veterinarian
mycophenolate mofetil for the treatment of pemphigus foliaceus 1984; 6: 109–12.
in dogs (Abstract). Veterinary Dermatology 2001; 12: 226. 87. Scott DW, Walton DK, Smith CA et al. Unusual findings in canine
72. Olivry T, Rivierre C, Murphy KM. Efficacy of cyclosporine for treat- pemphigus erythematosus and discoid lupus erythematosus. Journal
ment induction of canine pemphigus foliaceus. Veterinary Record of the American Animal Hospital Association 1984; 20: 579–84.
2003; 152: 53–4. 88. Bennett D, Kelly DF, Kirkham D et al. Two cases of pemphigus
73. Gomez SM, Morris DO, Rosenbaum MR et al. Outcome and com- erythematosus (the Senear–Usher Syndrome) in the dog. Journal
plications associated with treatment of pemphigus foliaceus in of Small Animal Practice 1985; 26: 219–27.
dogs: 43 cases (1994–2000). Journal of the Veterinary Medical 89. Griffies JD, Mendelsohn CL, Rosenkrantz WS et al. Topical 0.1%
Association 2002; 224: 1312–6. tacrolimus for the treatment of discoid lupus erythematosus and
74. Graham-Mize CA, Rosser EJ. Absorption, bioavailability and activ- pemphigus erythematosus in dogs. Journal of the American
ity of prednisone and prednisolone in cats. In: Hillier A, Foster AP, Animal Hospital Association 2004; 40: 29–41.
Kwochka KW, eds. Advances in Veterinary Dermatology, Vol. 5. 90. Gonsalves-Hubers T. Pemphigus erythematosus in a chow chow.
Oxford, UK: Blackwell Publishing, 2005: 152–8. Canadian Veterinary Journal 2005; 46: 925–7.
75. Helton-Rhodes K, Shoulberg N. Chlorambucil: effective therapeutic 91. Faircloth JC, Montgomery JK. A practitioner case report: pemphi-
options for the treatment of feline immune-mediated dermatoses. gus erythematosus in a cat. Feline Practice 1982; 12: 31–3.
Feline Practice 1992; 20: 5–8. 92. Wiemelt SP, Goldschmidt MH, Greek JS et al. A retrospective
76. Beale KM, Altman D, Clemmons RR et al. Systemic toxicosis study comparing the histopathological features and response to
associated with azathioprine administration in domestic cats. treatment in two canine nasal dermatoses, discoid lupus erythema-
American Journal of Veterinary Research 1992; 53: 1236–41. tosus and mucocutaneous pyoderma. Veterinary Dermatology
77. White SD, Rosychuk RAW, Outerbridge CA et al. Thiopurine 2004; 15: 341–8.
methyltransferase in red blood cells of dogs, cats, and horses. 93. Olivry T, Chan LS. Autoimmune blistering dermatoses in domes-
Journal of Veterinary Internal Medicine 2000; 14: 499–502. tic animals. Clinics in Dermatology 2001; 19: 750–60.
78. Foster AP, Shaw SE, Duley JA et al. Demonstration of thiopurine 94. Wurm S, Mattise AW, Dunstan RW. Comparative pathology of
methyltransferase activity in the erythrocytes of cats. Journal of pemphigus in dogs and humans. Clinics in Dermatology 1994; 12:
Veterinary Internal Medicine 2000; 14: 552–4. 515–24.
79. Peroni DL, Stanley S, Kollias-Baker C et al. Prednisone per os is 95. Aoki-Ota M, Nishifuji K, Amagai M et al. Distribution and expres-
likely to have limited efficacy in horses. Equine Veterinary Journal sion of desmosomal proteins, desmoglein-1 and – 3 in normal
2002; 34: 283–7. canine skin and mucous membrane. In: Thoday KL, Foil CS, Bond
80. Chan LS, Ahmed AR, Anhalt GJ et al. The first international con- R, eds. Advances in Veterinary Dermatology, Vol. 4. Oxford:
sensus on mucous membrane pemphigoid: definition, diagnostic Blackwell Publishing, 2002: 30–6.
Résumé Chez l’homme, la dénomination pemphigus regroupe un ensemble de dermatoses autoimmunes caractérisées
par une séparation intraépidermique résultant d’un détachement cellulaire par acantholyse. Ces entités sont classées en
se basant sur la profondeur du clivage épidermique, et des formes superficielles (pemphigus foliacé, pemphigus à IgA) et
des formes profondes (pemphigus vulgaire, pemphigus vegetant et pemphigus paranéoplasique) sont décrites. Chez les
animaux domestiques, des formes de pemphigus ont été rapportées depuis le milieu des années 70 et la classification
animale ressemble à celle utilisée chez l’homme. Cet article décrit les données récentes sur l’épidémiologie, les signes
cliniques, l’histopathologie, l’immunopathologie et le traitement des pemphigus superficiels chez les animaux domes-
tiques. Des données détaillées sur le pemphigus foliacé canin, félin, équin et caprin, sur le pemphigus érythémateux canin
et félin et sur le pemphigus panépidermique pustuleux canin sont présentées.
Resumen En humanos la denominación pénfigo engloba un grupo de enfermedades vesiculares de la piel con sepa-
ración intraepidermal resultando en desunión intercelular y acantolisis. Las entidades se clasifican en base al nivel de for-
mación de vesículas en la epidermis, y tanto variantes superficiales (pénfigo foliáceo, pénfigo con deposición de IgA) como
profundas (pénfigo vulgar, pénfigo vegetativo y pénfigo paraneoplástico) son reconocidas. En animales domésticos,
variantes de pénfigo han sido reconocidas desde la mitad de la década de 1970, y la clasificación de las enfermedades se
asemeja a la utilizada en seres humanos. Este artículo revisa el conocimiento actual sobre la epidemiología, signos clínicos,
304 © 2006 The Author. Journal compilation © 2006 European Society of Veterinary Dermatology.
15. Superficial pemphigus in domestic animals
histopatología, inmunopatología y resultados del tratamiento de las variantes de pénfigo superficial en animales domésticos.
Se ofrece asímismo una información detallada sobre pénfigo foliáceo en perros, gatos, caballos y cabras, pénfigo eritematoso
en perros y gatos, y pénfigo pustuloso panepidermal en perros.
Zusammenfassung Beim Menschen umfasst die Pemphigus-Bezeichnung eine Gruppe von autoimmunen blasen-
bildenden Hauterkrankungen mit intraepidermaler Separation, welche aus einer Zell-Zell Loslösung durch Akantholyse
resultiert. Die Gruppen werden nach dem Ausmaß der Blasenbildung in der Epidermis eingeteilt, wobei sowohl oberflächliche
(Pemphigus foliaceus, IgA Pemphigus) als auch tiefe (Pemphigus vulgaris, Pemphigus vegetans und paraneoplastischer
Pemphigus) Varianten anerkannt sind. Bei Haustieren sind Untergruppen von Pemphigus seit der Mitte der 1970er Jahre
bekannt, und die Klassifizierung der Erkrankung ist jener ähnlich, die für humane Patienten verwendet wird. Dieser Artikel
überarbeitet das neueste Wissen in bezug auf Epidemiologie, klinische Symptome, Histopathologie, Immunpathologie und
Behandlungserfolge von oberflächlichem Pemphigus bei Haustieren. Detaillierte Informationen über Pemphigus foliaceus
beim Hund, bei der Katze, beim Pferd und bei der Ziege, über Pemphigus erythematosus beim Hund und bei der Katze,
sowie über den panepidermalen pustulösen Pemphigus beim Hund werden geliefert.
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