Diagnosing New Autoimmune Blistering Skin Diseases
of Dogs and Cats
Thierry Olivry, DrVet, PhD, DipACVD, DipECVD, and
Hilary A. Jackson, BVM&S, DVD, MRCVS, DipACVD
Autoimmune blistering skin diseases have been recognized for
decades in humans and dogs. In the dog, most of these diseases
unfortunately were grouped under the generic denomination of
bullous pemphigoid without any confirmation that the autoanti-
bodies targeted bullous pemphigoid antigens. In recent years,
advanced diagnostic methods have permitted the recognition of
new autoimmune blistering skin diseases in humans and com-
panion-animal species. At this time, the diagnosis of these enti-
ties is made by combining clinical signs and results of histopa-
thology. Immunologic methods serve to establish the presence
of skin-fixed and circulating autoantibodies that target various
epidermal or basement membrane antigens. In this article, salient
features of the most common canine and feline subepidermal
blistering dermatoses (mucous membrane pemphigoid, bullous
pemphigoid, epidermolysis bullosa acquisita) and new variants
of cutaneous lupus (type I bullous systemic lupus erythematosus
and vesicular cutaneous lupus erythematosus) are presented.
Copyright © 2001 by W.B. Saunders Company
ecent advances in diagnostic techniques have led to the
R recognition of new disease entities in companion-animal
dermatology or a revision of the nomenclature for previously
recognized diseases. It is the intention of this chapter to review
the diagnostic features of newly described autoimmune blister-
ing skin diseases and to give a brief indication of the prognosis
and treatment.
General Methods of Diagnosis
Vesicles and bullae are rarely seen in companion-animal prac-
tice; more commonly, the secondary lesions of erosions, ulcer-
ation, and depigmentation are found. This spectrum of clinical
signs, however, should lead the practitioner to consider a list of
differential diagnoses that include autoimmune blistering skin
diseases.
Providing an "accurate" diagnosis is not only important from
an academic point of view, but it is also significant to provide
prognostic information and to select the most approprmte treat-
ment for the small-animal patient.
The following guidelines are designed to achieve this goal:
From the Department of Clinical Sciences, College of Veterinary Med-
icine, North Carolina State University, Raleigh, NC.
Address reprint requests to Thierry Olivry, DrVet, PhD, Department of
Clinical Sciences, College of Veterinary Medtcine, North Carolina State
University, 4700 HIllsborough Street, Raleigh, NC 27606.
Copyright © 2001 by W.B. Saunders Company
1096-2867/01/1604-0006535.00/0
doi:10.1053/svms.2001.26999
Climcal Techniques in Small Animal Practice, Vol 16, No 4 (November), 2001: pp 225-229
Collection of Signalment and Pertinent Historical
Information
Many of the autoimmune blistering skin &seases exhibit a
strong breed predisposition (eg, Great Danes and epidermolysis
bullosa acquisita [EBA], German shepherds and mucous mem-
brane pemphigoid [MMP] ; collies and Shetland sheepdogs and
vesicular cutaneous lupus erythematosus [VCLE]. Addition-
ally, VCLE appears to be photosensitive. Response to previous
therapy could allow to differentiate between glucocorticoid-
responsive (bullous pernphigoid [BP], MMP) or glucocorti-
cold-resistant (EBA) entities.
Recording of Clinical Signs
The location of lesions may orient toward different entities, for
example, mucous membranes are predominantly affected in
MMP, whereas areas of friction and trauma could suggest EBA.
Extensive abdominal erosions are found in VCLE. Tense vesi-
cles are seen commonly in BP and EBA, whereas flaccid vesicles
suggest VCLE.
Obtaining Skin Biopsy Specimens
The optimal sample is obtained from biopsies of vesicles and
bullae. If only erosions and ulcers are present, biopsy samples
should be obtained as a wedge encompassing both margins of
the erosive lesion. Many of the &seases discussed herein exhibit
fairly similar mmroscopic lesions (eg, subepidermal vesicles)
with some variations.
Histopathologic E x a m i n a t i o n of Skin Biopsy Specimens
On histopathologic examination of skin biopsy specimens, cell-
poor vesicles are usually suggestive of either MMP or early EBA.
Vesicles of BP are usually rich in eosinophils and neutrophils.
In VCLE, vesiculation occurs because of confluent lymphocyte-
mediated basal cel] vacuolation. Additionally, periodic acid-
Schiff or collagen IV staining reveal that vesiculation most often
occurs below the lamina densa in cases of EBA and bullous
systemic lupus erythematosus (BSLE), and above it in other
diseases.
Routine I m m u n o l o g i c Methods
Direct immunofluorescence (IF) or immunoperoxidase (IP)
methods can be performed on paraffin-embedded sections from
the same block that served for histopathology to demonstrate
skin-fixed autoantibodies. At this time, there is no need for
additional samples in "transport" medium (eg, Michel's me-
dium). Indirect IF techniques are useful for the detection of
circulating autoantibodies directed against epidermal keratin-
225
 TABLE 1. Diagnosing Mucous Membrane Pemphigoid in Dogs and Cats
• Clinical: vesicles, erosions, and ulcers predominate on mucosae or at mucocutaneous junctions
• Major differential diagnoses: cutaneous lupus variants, erythema multiforme variants, pemphigus vulgaris
• Histopathologic: subepidermal vesicles contain few inflammatory cells
• Immunologic: skin-fixed and/or circulating autoantibodies target various basement membrane antigens
ocytes or against the basement membrane zone. The use of
"salt-split substrates," in which the basement membrane has
been cleaved at the level of the lamina lucida upon incubation
of normal skin with 1 mol/L sodium chloride, will permit the
early differentiation of EBA and type I BSLE (autoantibodies
bind to the bottom of the clefts) from BP or MMP (autoantibod-
ies bind to the top of the clefts). 1
Advanced Immunologic Methods
Immunoblotting, immunoprecipitation, and/or enzyme-linked
immunosorbent assay (ELISA) are used to characterize the an-
tigens targeted by circulating autoantibodies. At this time, these
investigations are performed in few veterinary dermatology re-
search laboratories.
New Autoimmune Diseases of the Epidermal
Basement Membrane
In recent years, the classification of autoimmune basement
membrane blistering skin diseases has been modeled from that
proposed for human beings based on location of skin lesions
and identification of targeted antigens. Discussed herein are the
3 most common autoimmune subepidermal blistering diseases
of dogs and cats. 2
M u c o u s M e m b r a n e (Cicatricial) P e m p h i g o i d
Mucous membrane pemphigoid, also known as cicamcial pem-
phigoid, is a rare autoimmune disease of humans in which
lesions occur on mucosae or at mucocutaneous junctions be-
cause of autoantibodies directed against various basement
membrane proteins. In dogs and cats, MMP is the diagnosis
given to half of the patients diagnosed with autoimmune sub-
epidermal blistering diseases. 2 Diagnosing MMP requires com-
patible clinical, histopathologic, and immunologic findings
(Table 1).
Fig 1. Canine MMP. Depigmentation and erosions
present on the lower lip.
226
Dogs and cats are affected with MMP during adulthood,
sometimes before 1 year of age. 3,4 There is no recognized sex
predisposition. The German shepherd breed accounts for
~-30% of dogs diagnosed with MMP. 3 Lesions of MMP com-
prise vesicles, erosions, and ulcers that are seen primarily in or
around the oral cavity (Fig 1), nasal planum, eyes, ear canals,
anus, and genitalia. 3,4 Involvement of haired skin is uncommon
and, when present, usually is minimal. 3,4
Histopathologic examination of skin biopsy specimens will
reveal subepidermal vesiculation with few inflammatory cells
(Fig 2). 3'4
Immunologic tests are important to confirm the diagnosis of
MMP in dogs and cats. Detection of basement membrane-fixed
immunoglobulin G (IgG) autoantibodies is best made from
paraffin-embedded specimens submitted for histopathology,
and tested with direct IF or IP methods. Detection of basement
membrane-specific circulating IgG autoantibodies is achieved
by indirect IF testing of the patient's serum. The identification
of the targeted autoantigens (eg, collagen XVII or laminin-5)
necessitates advanced immunologic methods. 3,4
The prognosis of canine and feline MMP is variable. 3,4 In
some patients, lesions respond to the classical combination of
tetracycline and niacinamide, as reported recently. 2 In other
dogs, mucosal erosions only abate following combination im-
mune-suppressive therapy with glucocorticoids and cytotoxic
drugs. 3
Bullous P e m p h i g o i d
Bullous pemphigoid is an autoimmune blistering dermatosis of
humans characterized by autoantibodies specific for collagen
XVII epitopes and a clinical presentation of vesicles predomi-
nating on haired skin. In dogs and cats, BP is the second-most
common autoimmune subepidermal blistering skin disease. 2
As for MMP, the diagnosis of canine and feline BP relies on
Fig 2. Canine MMP. Dermoepidermal separation occurs be-
are low the epidermis (arrowhead), and there is sparse dermal
inflammation.
OLIVRY AND JACKSON
 TABLE 2. Diagnosing Bullous Pemphigoid in Dogs
and Cats
• Clinical: tense vesicles, erosions, and crusts predominate on
nonmucosal skin
• Major differential diagnoses: EBA, pemphigus variants, VCLE
• Histopathologic: subepidermal vesicles are rich in neutrophils and
eosinophils
• Immunologic: circulating autoantibodies target, at least, the
NC16A segment of type XVll collagen
clinical, histopathologic, and immunologic observations (Ta-
ble 2).
Dogs and cats can be affected with BP at any age, sometimes
soon after puberty. 2,5 Sex and breed predispositions have not
been identified at this time. Skin lesions comprise tense vesi-
cles, erosions, and crusts that occur on haired skin (Fig 3), and
less commonly on mncosae or mucocutaneous junctions.2, 5
Oral involvement is seen in less than one third of the cases. 2,5 In
fact, the scarcity of mucosal/mucocutaneous involvement in BP
is the main criterion that differentiates it from MMP.
The diagnosis of BP is supported by the biopsy of intact
vesicles. Histopathologic examination will reveal subepidermal
vesiculation rich m eosinophils and neutrophils (Fig 4), 2,5
Immunologic tests are necessary to confirm the diagnosis of
BP in dogs and cats. Direct and indirect IF findings are identical
to those of most patients with MMP. The confirmation of the
presence of circulating autoantibody targeting canine collagen
XVII (NC16A segment) is best made with an ELISA. This test
will be made available commercially in the near future. 3,6
The prognosis of BP is good for most canine and feline pa-
tients. 2 The first line of treatment should consist of tetracycline
(doxycycline) with or without niacinamide. In case of lack of
response to this regimen, then glucocorticoid monotherapy
should be attempted. 2
Epidermolysis Bullosa Acquisita
In humans and dogs, EBA is a rare autoimmune blistering skin
disease usually characterized by severe clinical signs and a poor
prognosis. It is associated, immunologically, with autoantibod-
ies that target collagen VII. Due to the severity of the skin
lesions, the diagnosis of EBA must be made rapidly by corn-
Fig 3. Canine BP. There area tense vesicles, often hemor-
rhagic, with erosions and crusts on the concave aspect of
the ear pinna.
BLISTERING SKIN DISEASES
j "7~-J-
Fig 4. Canine BP. Subepidermal vesiculation arises in direct
association with dermal neutrophilic and eosinophilic micro-
abscesses (arrowhead).
bining clinical, histologic, and immunologic information
(Table 3).
In the dog, EBA is the diagnosis given to one fourth of the
patients with basement membrane-specific autoantibodies. 2
The generalized inflammatory form of canine EBA is seen most
commonly in Great Danes. 2,r In this breed, dogs can be affected
around 1 year of age. 2,r There is no recognized sex predisposi-
tion.
The generalized inflammatory form of canine EBA is charac-
terized by tense vesicles that arise from erythematous patches
and wheals. 2,r Erosions occur rapidly at sites of friction, notably
in the axillae (Fig 5) and groin. There is extensive sloughing of
the oral epithelium and of the footpads. Lethargy and fever can
be seen, especially in case of secondary bacterial sepsis.2, r There
is a very rare localizedform of canine EBA in which few vesicles
are found. 8 This form is not associated with systemic signs.
The diagnosis of EBA must be confirmed by skin biopsy
collection of vesicles or erythematous patches. Histopathologic
examination will reveal subepidermal vesicles without inflam-
mation or with prominent subepidermal alignment of neutro-
phils and subepidermal microabscesses (Fig 6). 2,r,8
Testing of skin samples and serum by routine direct or indi-
rect IF will be similar to that of dogs with BP or MMP. 2,r,s
Advanced immunologic tests will reveal, however, that EBA
autoantibodies bind to the lower part of the epidermal base-
ment membrane zone and that they recognize a segment of
collagen VII. 2,r,s
The prognosis of inflammatory generalized canine EBA is
very poor, because lesions rarely respond to immune-suppres-
sion, even with glucocorticoids and cytotoxic drugs. In this
form, dogs are usually euthanatized because of lack of response
to therapy.
TABLE 3. Diagnosing Epidermolysis Bullosa Acquisita
in Dogs
• Clinical: erythema, tense vesicles followed by severe erosions and
ulcerations, especially in areas of friction (generalized inflammatory
form); rare tense vesicles (localized form)
Major differential diagnoses: bullous pemphigoid, pemphigus
vulgaris, VCLE
Histopathologic: subepidermal vesicles, often rich in neutrophils
Immunologic: circulating autoantibodies target the NC1 segment of
type VII collagen
227

Fig 5. Canine EBA. Severe erosions can be seen on the axilla
of a Great Dane with the generalized inflammatory form of
the disease.
New Vesicular Variants of Cutaneous Lupus
Erythematosus
Type I BSLE
In human patients with systemic lupus erythematosus (SLE),
cutaneous subepidermal blistering can occur because of the
individual's production of antibodies specific for basement
membrane antigens, including the EBA (collagen VII) antigen.
This condition is referred to as type I BSLE. This entity is, in
summary, EBA that occurs during SLE.
In one Bichon frise, the diagnosis of type I BSLE was pro-
posed because of the fulfillment of the following criteria: a
diagnosis of SLE by standard methods; an acquired, vesicular,
erosive, and ulcerative eruption; microscopic subepidermal
vesicles with neutrophil-predominant inflammation at the
dermo-epidermal junction; IgG deposition at the epidermal
basement membrane zone; and anti-type VII collagen circulat-
ing IgG autoantibodies. 9
VCLE
VCLE is the denomination recently proposed to replace the
name "idiopathic ulcerative dermatosis of collies and shel-
ties." ~oThis entity exhibits clinical and histopathologic similar-
Fig 6. Canine EBA. There is subepidermal vesiculation with a
high number of neutrophil granulocytes (arrowhead).
228
TABLE 4. Diagnosing VOLE in Dogs
• Clinical: annular to polycyclic erythema leading to flaccid vesicles
and erosions on hairless areas of rough collies, Shetland
sheepdogs, and their crosses
• Major differential diagnoses: bullous pemphigoid, EBA, erythema
multiforme variants, dermatomyositis
• Histopathologic: lymphocyte-rich interface dermatitis with
intrabasal vesiculation
ities with a vesicular form of subacute cutaneous lupus ery-
thematosus of humans. Diagnosing canine VCLE requires com-
patible clinical and histopathologic findings (Table 4).
VCLE affects predominantly adult collies and Shetland
sheepdogs and their crosses. In one case series, females repre-
sented 6 of 8 reported cases. ~° In most dogs, the onset of lesions
occurs during summer months, suggesting that environmental
factors (eg, sunlight) could trigger cutaneous lesions.
Dogs affected with VCLE exhibit annular to polycyclic ery-
thematous patches that rapidly evolve into flaccid vesicles and
widespread erosions and ulcerations (Fig 7). l° These lesions
are observed predominantly on hairless areas of the ventral
abdomen, axillae, medial thighs, and concave pinnae, to Lesions
are often extensive, and secondary sepsis can be a complication.
Microscopic examination of skin biopsy specimens reveals a
cell-rich interface dermatitis in which lymphocyte-mediated
keratinocyte killing results in confluent basal cell vacuolation
and vesicle formation (Fig 8)3 0 Immunologic characterization
of canine VCLE is currently underway.
Affected patients should be given a guarded prognosis. In
most cases, long-term therapy with immunosuppressive doses
of glucocorticoids is required, whereas a combination of ste-
roids with other chemotherapeutic drugs can be necessary in
other patients.
Conclusions
Being familiar with clinical features of these novel blistering
skin diseases should allow veterinary practitioners to provide a
more accurate diagnosis and prognosis for affected patients and
select the most appropriate medications for their patients. At
this time, it is important to realize that clinical diagnosis must
be supported by histopathology, and that appropriate selection
Fig 7. Canine VCLE. Annular to polycyclic erythematous
patches with central ulceration and flaccid vesiculation are
present on the abdomen of a rough collie.
OLIVRY AND JACKSON

Fig 8. Canine VOLE. Lymphocyte-mediated interface derma-
titis results in confluence of basal keratinocyte cytolytic
vacuoles and causes intraepidermal vesicles (arrowhead).
of biopsy material is critical in achieving accurate diagnosis.
Additionally, biopsy samples should be submitted to a veteri-
nary dermatopathologist familiar with these diseases. Ad-
vanced immunologic tests are expected to become more widely
10. Jackson HA, Oltvry T: Ulcerative dermatosis of the Shetland sheep-
available within the coming years, and will thus facilitate the
identification of the various disease subsets.
BLISTERING SKIN DISEASES
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