vet dermatol mucous membrane pemphigoid in …for example, lichen planus, pemphigus vulgaris,...
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Mucous membrane pemphigoid in dogs: a retrospectivestudy of 16 new cases
Heng L. Tham*, Thierry Olivry*†, Keith E. Linder†‡ and Petra Bizikova*†
*Department of Clinical Sciences, College of Veterinary Medicine, †Comparative Medicine Institute and ‡Department of Population Health and
Pathobiology, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Drive, Raleigh, NC 27607, USA
Correspondence: Petra Bizikova, Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, 1060 William
Moore Drive, Raleigh, NC 27607, USA. E-mail: [email protected]
Background – Mucous membrane pemphigoid (MMP) is a chronic autoimmune subepidermal blistering disease
of dogs, cats and humans.
Objectives – The goal of this study was to describe the clinical, histological and immunological features and
treatment outcomes of canine MMP.
Animals – Sixteen dogs were diagnosed with MMP based on the presence of mucosal- or mucocutaneous-pre-
dominant vesiculation and/or ulceration, histological confirmation of subepidermal clefting and an age of disease
onset greater than 6 months.
Results – Six of 16 dogs (38%) were German shepherd dogs and their crosses. The median age of disease onset
was 6 years (range: 1–10 years). At the time of presentation, the dogs exhibited erosions and ulcers in the oral
cavity (11 of 16; 69%), nasal (nine of 16; 56%), periocular (eight of 16; 50%) and genital (six of 16; 38%) regions.
Haired skin lesions were less frequent (six of 16; 38%) and involved mostly concave pinnae. Information on treat-
ment outcome was available for 11 dogs (69%). A complete remission (CR) of lesions was achieved in 10 of 11
dogs (91%). The median time to CR was 33 weeks (range: 6–64 weeks). Treatment regimens varied widely but
six of 10 (60%) dogs received a combination of tetracycline antibiotic and niacinamide alone, or with another
drug, at the time of CR. Forty percent of the dogs in which CR had occurred experienced lesion relapse upon drug
dose reduction.
Conclusions and clinical importance – Canine MMP is a chronic and relapsing disease requiring long term
treatment. Combination therapy is often needed to achieve CR.
Introduction
Mucous membrane pemphigoid (MMP), also known as
cicatricial pemphigoid, is a chronic autoimmune subepi-
dermal blistering disease (AISBD) recognized in humans,
dogs and cats.1–4 In all of these species, it is character-
ized by a variable combination of vesicles, ulcerations and
scarring affecting predominantly mucosae and mucocuta-
neous junctions. Although exact epidemiological data on
canine MMP are unavailable, this disease is considered to
be the most common AISBD in this species, with German
shepherd dogs appearing to be an over represented
breed.2
In humans and animals, MMP is associated with the
presence of circulating autoantibodies that target variable
antigens of the basement membrane zone (BMZ); these
include collagen XVII (BP180), BPAG1e (BP230), integrin
a6/b4, laminin-332 and, more rarely, collagen VII.1–4 The
demonstration of skin fixed-antibodies and/or activated
complement and/or the presence of circulating anti-BMZ
antibodies is proposed as one of the diagnostic criteria for
MMP in humans.4 Likewise, it has been suggested that,
if available, the demonstration of anti-BMZ antibodies
and/or complement should be part of the diagnostic crite-
ria for the diagnosis of MMP in dogs.2 Nonetheless, due
to autoantigen overlap among the AISBDs, the demon-
stration of an elevated titre of anti-BMZ antibodies would
not help distinguish MMP from other AISBDs.5–7 Further-
more, in humans, especially when appropriate biopsy
cannot be obtained, the presence of anti-BMZ antibodies
is used predominantly to eliminate other blistering dis-
eases that do not affect the BMZ directly; these include,
for example, lichen planus, pemphigus vulgaris, erythema
multiforme/Stevens Johnson syndrome and angina bul-
losa haemorrhagica.6
In humans, the treatment of MMP depends on the
“risk group” into which patients are classified. This classi-
fication is based on the severity, extent and location of
lesions (i.e. “low-risk” group: oral involvement with or
without skin lesions; “high-risk” group: eye, genital, res-
piratory tract and upper gastrointestinal tract lesions).4
Because of the better prognosis in low-risk patients, the
treatment is usually more conservative and utilises drugs
such as topical glucocorticoids with or without oral low-
dose glucocorticoids, tetracycline/niacinamide or dap-
sone.8,9 In contrast, patients in the high-risk group are
treated with more potent drugs from the onset to avoid,
or reduce, the irreversible scarring and strictures associ-
ated with this disease. In this group, the use of systemic
Accepted 16 April 2016
Sources of funding: This study was self-funded.
Conflict of interest: No conflicts of interest have been declared.
© 2016 ESVD and ACVD, Veterinary Dermatology, 27, 376–e94.376
Vet Dermatol 2016; 27: 376–e94 DOI: 10.1111/vde.12344
drugs is mandatory and a combination of adjunctive
immunosuppressive medications such as high-dose glu-
cocorticoids, azathioprine, cyclophosphamide and/or
intravenous immunoglobulin (IVIG) infusions are often
used.8,9 Unfortunately, because of the chronic and pro-
gressive nature of the disease and its tendency to
relapse, MMP is challenging to manage in people, and
the reported treatment success rates can vary greatly.10
Because of the rarity of MMP in dogs, only limited
information about the treatment and outcome of this dis-
ease is available. To the best of the authors’ knowledge,
there is only a single publication discussing the treatment
outcome of 11 dogs with MMP.2 More information about
canine MMP will assist to better understand this syn-
drome and improve our ability to successfully manage
this chronic, frequently relapsing disease.
The objectives of this study were as follows: (i) to
report information regarding the signalment, clinical pre-
sentation, histological and immunological features of
additional cases of canine MMP; and (ii) to assess the
therapeutic interventions and treatment outcomes in
dogs with MMP.
Material and Methods
Case selectionDogs included in this study were selected from: (i) cases whose sera
were tested in our immunodermatology laboratory between 2003
and 2014; (ii) cases diagnosed with MMP by veterinary clinicians at
the North Carolina State University (NCSU) between 2003 and 2014,
and (iii) cases identified through an e-mail sent to the Vetderm Inter-
net list ([email protected]) between February 2014 and August
2014.
Only dogs that fulfilled all three criteria listed below were included
in the study:
1 Clinical observations of mucosal- or mucocutaneous-predomi-
nant vesiculation and/or ulceration.
2 Histopathological findings of subepidermal vesiculation/sepa-
ration and exclusion of other pathologies resulting in an epider-
mal detachment (suprabasal acantholysis, interface dermatitis,
epidermal necrotizing diseases) in a biopsy report.
3 Disease onset >6 months of age.
Because of the immunological heterogeneity of canine MMP and
the lack of ability of direct and indirect immunofluorescence (IF) to
distinguish MMP from other AISBDs, positivity for either or both of
these tests was not required as additional inclusion criterion.6,7
In order to obtain information about history, signalment, clinical
signs, treatment and outcome, referring veterinarians were asked to
complete an ad hoc questionnaire and submit clinical images of the
cases whenever available. Medical records, including histopathology
reports and clinical images, were reviewed for all cases diagnosed at
NCSU and the Vetderm Internet list cases. The treatment outcome
was based on findings obtained during the last available physical
examination of the affected dog, and focused on reporting informa-
tion on the number of dogs in which a complete remission (CR) of
the disease had been achieved or those with lesions that failed to
respond to the treatment. A CR was defined as the absence of new
lesions or the complete healing of existing ones, whereas a “failure
of therapy” was defined as an inability to control disease activity (i.e.
a continuous development of new lesions, an extension of old
lesions or a lack of healing). In dogs lost to follow-up, the treatment
outcome was based on clinical findings recorded during their final
visit.
HistopathologySixteen cases had histopathological findings reported of subepider-
mal vesiculation/separation (the primary histopathological inclusion
criterion), based on the assessment of their primary histopathology
report. If available, tissue blocks and/or histological sections of biop-
sies were requested from clinicians that contributed cases to the
study. Tissue samples from 11 dogs were available for further
review by one of the authors. Histological sections were stained
with haematoxylin and eosin and evaluated as described previ-
ously.11
Detection of tissue-bound and circulating anti-
basement membrane zone autoantibodiesTissue deposits of IgG, IgM and IgA antibodies and activated C3
complement at the BMZ of the lesional and perilesional skin were
detected using direct IF performed on paraffin-embedded skin sam-
ples with minor variations from the technique described earlier.12
The source and dilution of immunoreagents had varied over time due
to the 11 year span of this retrospective study.
The detection of circulating anti-BMZ IgG and IgA antibodies was
performed by indirect IF on salt-split buccal mucosa collected from
healthy dogs euthanized at a local shelter or as part of other research
protocols using a previously published protocol.13 For the detection
of IgE autoantibodies, a secondary monoclonal mouse anti-dog IgE
antibody (clone 5.91, Bruce Hammerberg, NCSU Raleigh; NC, USA)
was used. Sera from affected dogs were collected during phases of
active disease. All patient sera were tested at serial dilutions ranging
from 1:10 to 1:2,500 for IgG, 1:10–1:40 for IgA and 1:10–1:50 for IgE
and IgM. Sera from normal healthy dogs served as negative controls.
A result was deemed positive if a linear fluorescence pattern could
be detected at the level of the BMZ. The location of the antibody
binding was further specified as dermal, epidermal or mixed depend-
ing on whether the fluorescence was detected on the bottom, on the
roof or on both sides of the salt-split buccal mucosa section, respec-
tively.
Results
Signalment
Sixteen dogs fulfilled the inclusion criteria and were
included in this study. Two dogs were diagnosed with
MMP at NCSU, ten dogs were referred for further testing
in our immunodermatology laboratory between 2003 and
2014, and four dogs were received as a response to a
Vetderm Internet list search performed between Febru-
ary and August 2014. Of these 16 dogs, 12 (75%) were
purebreds and four (25%) were crossbred dogs. Six
(38%) were German shepherd dogs and their crosses;
two (13%) were poodles and their crosses, and there
was one each of the following breeds: Shetland sheep-
dog, English springer spaniel, pug, Rhodesian ridgeback,
giant schnauzer and Rottweiler. The female-to-male sex
ratio was 1.
The median age of onset of skin lesions was 6 years
(range: 1–10 years). Four dogs (25%) developed lesions
in early adulthood (between 1 and 3 years of age). Eight
of the 16 dogs (50%) developed lesions in mid-adulthood
(between 4 and 7 years of age) and the remaining four
dogs (25%) had the onset of lesion in late adulthood
(8 years and older).
Odds ratios for breed, sex or age predispositions to
develop MMP could not be calculated because included
dogs were from various continents and a control popula-
tion was therefore not available.
© 2016 ESVD and ACVD, Veterinary Dermatology, 27, 376–e94. 377
Canine mucous membrane pemphigoid
Clinical summary
Skin lesions were symmetrical in 14 of 16 dogs (88%)
and they consisted of erosions and ulcers (16 of 16 dogs;
100% – an inclusion criterion), crusting (nine of 16; 56%),
erythema (five of 16; 31%), vesicles/bullae (five of 16;
31%) (Figure 1a), scarring (three of 16; 19%) and
hypopigmentation (two of 16; 13%).
The body regions first reported to be affected by
lesions were oral/perioral (12 of 16; 75%), ocular/perioc-
ular (six of 16; 38%), nasal (four of 16; 25%) and geni-
tal (two of 16; 13%) regions and/or concave pinnae
(two of 16; 13%). At the time of presentation to the
veterinarian, all dogs (100%) exhibited lesions on muco-
sae or mucocutaneous junctions assuming the nasal
planum to be a modified mucosa. Fifteen dogs exhib-
ited lesions on two or more mucosae or mucocuta-
neous junctions (median: 3, mean: 3). Haired skin
involvement was less common (six of 16; 38%). The
distribution of lesions at the time of diagnosis is sum-
marized in Table 1 and representative lesions are
shown in Figure 1.
Nondermatological complaints reported in six of 13
dogs (46%) were associated with the oral cavity and con-
sisted of malodour (two dogs), pain when eating (two
dogs) and excessive salivation/drooling (two dogs). A
loss-of-function of affected organs secondary to chronic
scarring (e.g. blindness, genital strictures, breathing diffi-
culties) was not reported in any of the dogs.
Treatment and outcome
Information about the treatment and outcome was avail-
able for 11 dogs (69%). The remaining five dogs were lost
to follow-up immediately after diagnosis. The median
time of follow-up was 50 weeks (range: 3–231 weeks). A
CR of MMP was achieved in 10 of 11 dogs (91%); the
median time to CR was 33 weeks (range: 6–64 weeks).
A spontaneous remission of MMP was not seen in any
patient.
Treatment regimens varied widely between dogs and
they included the following drugs: glucocorticoids, tetra-
cycline antibiotics (i.e. doxycycline or tetracycline), niaci-
namide, azathioprine, ciclosporin (with or without
ketoconazole), dapsone, colchicine, topical glucocorti-
coids and tacrolimus. These drugs were used either as
monotherapy (one of 11; 9%) or in various combinations
(10 of 11; 91%) (Table S1). Nine dogs (82%) were treated
with two or more drugs throughout the entire treatment
period (from initial diagnosis until CR). At the time when
a b
c d
Figure 1. Representative lesions of canine mucous membrane pemphigoid (MMP): (a) bulla and ulceration in the oral cavity and lip (Case 16; cour-
tesy of Sandra Sargent); (b) nasal crusting, depigmentation and scarring (Case 12, NC State University); (c) ruptured vesicles and ulceration on the
gingiva (Case 12); and (d) ulcerations and scarring of the hard palate (Case 12).
© 2016 ESVD and ACVD, Veterinary Dermatology, 27, 376–e94.378
Tham et al.
CR was documented, the majority of dogs (six of 10;
60%) were receiving a tetracycline antibiotic and niaci-
namide alone or in combination with another drug
(Table 2). Complete remission was also obtained in the
single dog treated with oral glucocorticoid monotherapy.
The topical use of glucocorticoids and tacrolimus was
reported in three (27%) and two (18%) of 11 dogs,
respectively. Of these, two of 11 dogs (18%) were trea-
ted with topical therapy at the time when CR was
achieved.
Oral glucocorticoid monotherapy was the most fre-
quent treatment regimen that failed to induce CR (five of
11; 45%) (Table S2).
No single treatment protocol appeared to be associated
with a more rapid disease remission. All 10 dogs in which
CR was obtained were maintained on a tapered dosage
regimen of their respective drug therapies; none of these
dogs had their treatment withdrawn. Four dogs (40%)
experienced a recurrence of MMP with a median time to
relapse of 12 weeks (range: 1–40 weeks). Of these four
dogs, three (75%) relapsed when treatment was tapered
(2 dogs) or withdrawn (1 dog), whereas one dog was
receiving the initial treatment regimen when the relapse
occurred.
Histopathology
For 11 dogs, skin biopsy material was available for
further review, with 2–20 histological sections of
mucocutaneous junctions, mucosae and/or haired skin
per dog. Vesicles were formed by subepidermal clefts
(Figure 2a), the majority of which were ruptured and bor-
dered an ulcer. Vesicles ranged from very small to large,
occasionally spanning the width of the biopsy, and/or
involved follicular infundibula. Most vesicles were empty;
however, a rupture of the majority of vesicles limited eval-
uation of vesicle contents for inflammatory cells, haemor-
rhage and fibrin. Subepidermal microvacuoles along the
BMZ were uncommon and mild (two of 11; 18%) or, less
often, marked (one of 11; 9%). A superficial dermal or
submucosal band of fibrosis (seven of 11; 64%) was com-
mon below vesicles, or below intact epithelium near vesi-
cles (Figure 2b), and ranged from mild to marked.
Fibrosis was reorganizing or sometimes had numerous
small blood vessels and shared features with a thin band
of granulation tissue. Biopsies with and without fibrosis
were seen in the same case.
Dermal and submucosal inflammation varied greatly in
the extent and type of inflammatory cells present.
Perivascular inflammation was occasionally mild and
often moderate to marked. Marked inflammation was
typically associated with a mucosa, chronic ulceration
and/or secondary bacterial infection characterized by
neutrophilic crusts, luminal neutrophilic folliculitis and
bacterial colonization. Mucosal and mucocutaneous
inflammation sometimes formed a band-like infiltrate of
lymphocytes and plasma cells just below the epithelium
(a lichenoid infiltrate). In at least one biopsy from each
dog, mild and occasionally moderate amounts of dermal
neutrophils (eight of 11; 73%) and eosinophils (six of 11;
55%) below vesicles or intact epithelium were present.
Lymphocytes and plasma cells were common and ranged
from mild to marked, when present. However, inflamma-
tion did not appear to localize to (target) the BMZ in most
cases (nine of 11; 82%). Rowing of individual neutrophils
along the BMZ was uncommon (one of 11; 9%) as was
rowing of histiocytes along the BMZ (two of 11; 18%),
but when present these changes were moderate to
marked. Lymphocytic exocytosis was common (nine of
11; 82%) and was mostly mild but sometimes moderate.
A few lymphocytes infiltrated infundibula and external
root sheath epithelium of hair follicles in one dog.
Regular epidermal or mucosal hyperplasia was com-
mon (11 of 11; 100%) and was most often moderate.
Although apoptosis of basal, and less often suprabasal,
keratinocytes was common (nine of 11; 82%), apoptosis
Table 1. Lesion distribution at the time of diagnosis in 16 dogs with
mucous membrane pemphigoid (MMP)
Affected areas
Number of
dogs Percentage
Mucosae/
mucocutaneous
junctions
Oral cavity 11 69%
Gingiva 10 of 11 91%
Hard/soft palate 9 of 11 82%
Tongue 4 of 11 36%
Labial/perilabial 9 56%
Nasal planum/
perinasal
9 56%
Eyelids 8 50%
Genitalia 6 38%
Anus/perianal 4 25%
Haired skin Concave pinnae 5 31%
Pressure points 2 13%
Periungual 1 6%
Note: For this disease and based on previous experience, the nasal
planum was considered to be a modified mucosa; the affected pres-
sure points in both cases were elbows.
Table 2. Drugs received by 10 dogs with mucous membrane pemphigoid (MMP) at the time when complete remission had been achieved
Number
of drugs
Number
of dogs
% (10 dogs
total)
Oral Topical
GC
Tetracycline
antibiotics NIAC AZA CSA KTZ DAP COLC GC TAC
1 1 10% X
2 2 20% X*† X
1 10% X X
1 10% X X
3 2 20% X X X
1 10% X X X
4 1 10% X X X X
1 10% X X X X
Abbreviations: GC, glucocorticoids; Tetracycline antibiotics (*tetracycline, †doxycycline); NIAC, niacinamide; AZA, azathioprine; CSA, ciclosporin;
KTZ, ketoconazole; DAP, dapsone; COLC, colchicine; TAC, tacrolimus.
© 2016 ESVD and ACVD, Veterinary Dermatology, 27, 376–e94. 379
Canine mucous membrane pemphigoid
usually only involved rare individual keratinocytes, and
only in a few cases was apoptosis numerous enough to
be warrant a mild grade. Vacuolation of basal ker-
atinocytes was not a feature. Pigmentary incontinence
was absent or ranged from mild to marked, but many sec-
tions lacked epidermal pigment to disperse to the dermis.
Detection of tissue-bound and circulating anti-BMZ
autoantibodies and complement
The detection of tissue-bound IgG, IgM, IgA antibodies
and C3 complement using direct IF was performed in 13
dogs. Twelve of these 13 samples (92%) exhibited a lin-
ear deposition of IgG along the BMZ. The only dog with
negative direct IF (Case 15) tested positive for circulating
anti-BMZ IgG. Basement membrane-bound IgA, IgM (Fig-
ure 3a) and C3 were detected in one (8%), four (31%)
and two (15%) cases, respectively.
Sera from 11 dogs were available for detection of
circulating anti-BMZ IgG, IgA and IgE antibodies. A
positive deposition of circulating IgG antibodies in the
form of a linear fluorescence deposit at the BMZ of
the salt-split buccal mucosa was detected in eight of
11 (73%) sera. The binding of these circulating IgG
autoantibodies was nearly always restricted to the epi-
dermal side of the salt-split mucosa (seven of eight;
88%) (Figure 3b), or it was observed on both epider-
mal and dermal sides (one of eight; 13%). One of the
three dogs without detectable circulating anti-BMZ IgG
had detectable tissue-bound anti-BMZ IgG (Case 1).
Tissues from the other two dogs with negative indirect
IF were not available for direct IF staining (cases 3 and
4). Circulating anti-BMZ IgA and IgE antibodies were
not detected in any of the 11 dogs.
Discussion
Although MMP is the most common AISBD in dogs, the
overall rarity of this condition limits our knowledge about
this entity, especially regarding the treatment and progno-
sis.1,2,7 Therefore, the goal of our retrospective study
was to provide additional information about the clinical,
histological and immunological aspects of this syndrome,
with an emphasis on treatment and outcome. This study
adds 16 new cases of canine MMP to those previously
published.1,2
a
b
Figure 3. Representative immunofluorescence (IF) results depicting
anti-BMZ (basement membrane zone) autoantibody deposit. (a)
Direct IF: linear and continuous deposit of IgM (arrowhead) at the
BMZ (Case 5); fluorescent spots in the superficial submucosa repre-
sent plasma cells secreting IgM. (b) Indirect IF on salt-split buccal
mucosa: circulating IgG autoantibodies target antigen(s) present on
the epidermal side of the clefts (arrowhead) (Case 5).
a b
Figure 2. Histopathology of canine mucous membrane pemphigoid (MMP): (a) a large subepidermal cleft devoid of inflammatory cells is present
at the margin of an ulcer (Case 5); and (b) a band of fibrosis (asterisk) is present just below the mucosa in an area lacking a submucosal cleft (Case
10). Haematoxylin and eosin.
© 2016 ESVD and ACVD, Veterinary Dermatology, 27, 376–e94.380
Tham et al.
The analysis of the signalment of these 16 dogs with
MMP is consistent with the previously reported finding
that the German shepherd dog is a frequently affected
breed.2 A possible breed predisposition for MMP is pre-
dictable, as genetics have been linked to the susceptibility
of development of many autoimmune diseases in people,
including MMP.6 Unfortunately, the relative risk for devel-
opment of MMP in German shepherd dogs could not be
calculated because a control population was not available
for such comparison.
The female-to-male ratio in this study was one, which
is in contrast to the previously reported data where males
were more often affected than females.2 The reason for
this disparity is unknown, although the relatively small
sample size compared to that of the previous meta-analy-
sis could have prevented the detection of a subtle differ-
ence in the ratio.2 Interestingly, in people with MMP,
women appear to be affected more often than men by a
factor of 1.5 to 2.14
Although the median age of the disease onset reported
in this study was similar to that of the previous meta-ana-
lysis, most dogs in this study developed the initial signs
of MMP in their mid-adulthood (i.e. aged 4–7 years).2 This
latter finding was in contrast to the data reported in the
previous review in which dogs generally developed the
disease during their late adulthood (older than 7 years).2
It is possible that increased awareness of this disease
over the past decade has led to an earlier detection of
clinical lesions and confirmation of the diagnosis. In
humans, MMP is a disease of elderly people with a mean
age of onset between 60 and 80 years.6,14
Most dogs in our study presented initially with oral and/
or perioral lesions, an observation similar to that reported
in the previous study.2 Over the course of the disease,
this region remained the most commonly affected site,
although most dogs developed lesions affecting other
mucosae or mucocutaneous junctions. Indeed, over 90%
of dogs exhibited lesions affecting two or more mucosae
or mucocutaneous junctions, a feature also reported in
previous cases of canine MMP.2 In a similar way to dogs,
oral cavity lesions are present in almost all human
patients (85%) with MMP.6 Ninety one percent of dogs
with oral involvement had lesions on the gingiva, which
early in the course of disease could lead to the misdiagno-
sis of MMP as another ulcerative gingival disease.15 Peo-
ple affected with MMP often develop blisters on the
nasal mucosa, larynx, pharynx or oesophagus. Although
none of the dogs in this study exhibited signs suggesting
such involvement, an endoscopic examination was not
performed in any of the dogs.
The nasal planum appeared to be the second most
common area to be affected (nine of 16; 56%); it was also
the third most common area in which the initial lesions
were reported to develop (four of 16; 25%). Dogs with
this lesion distribution could be misdiagnosed clinically as
having discoid lupus erythematosus (DLE). However,
facial DLE rarely affects the oral cavity and this alone dis-
tinguishes MMP from facial DLE.16–18
Our study did not reveal any apparent correlation
between the location of lesions, their severity or the num-
ber of affected sites and disease prognosis. In contrast,
people affected with ocular, laryngeal, genital or
oesophageal MMP tend to have poorer prognosis due to
the possibility of a functional impairment of these tissues
(e.g. blindness in ocular MMP, breathing difficulties in
nasal MMP, sexual dysfunction in genital MMP).6 The
location of lesions, their severity and the speed of the pro-
gression are important factors dictating the nature of the
treatment approach in human MMP.4,9 For example, on
one hand, people with severe ocular, genital, oesopha-
geal and/or laryngeal MMP usually are treated with sys-
temic immunosuppressive drugs such as glucocorticoids,
cyclophosphamide, azathioprine, mycophenolate mofetil
or, in refractory cases, with intravenous immunoglobulins
and/or biologics such as chimeric anti-CD20 antibody. On
the other hand, the initial treatment proposed to people
with mild disease involves topical glucocorticoids, dap-
sone or tetracycline antibiotics with niacinamide.4,9
In this study, CR was obtained in 60% of dogs that
received tetracycline antibiotics and niacinamide alone or
in combination with another immunosuppressive drug.
Likewise, five of 11 dogs (46%) included in the previous
review of canine MMP had had a partial or complete reso-
lution of clinical signs with a combination of tetracycline
and niacinamide;2 combining these data suggests that
this combination alone or with additional immunosuppres-
sive drugs should be considered as a first-line treatment
for canine MMP. Although the exact pathogenesis of
MMP remains unknown, several lines of evidence sug-
gest that antibody-mediated, complement-dependent as
well as complement-independent pathways play a role in
the dermoepidermal separation occurring in this dis-
ease.6,14 The first pathway is initiated by the binding of
autoantibodies to the BMZ antigen(s), which leads to acti-
vation of complement, mast cell degranulation, recruit-
ment of polymorphonuclears and BMZ injury by released
proteases.6 In addition, there is increasing evidence that
complement-independent processes involving ker-
atinocytes, proteases and/or endocytosis with subse-
quent degradation of the components of the BMZ could
be involved in blister formation.19,20 Similar mechanisms
leading to complement-independent blister formation
have been investigated in human bullous pemphigoid
(BP).21,22 The inhibitory effect of tetracycline antibiotics
and niacinamide on the activity of proteases, along with
their wide range of antiinflammatory properties (e.g. inhi-
bition of leukocyte chemotaxis and proinflammatory
cytokines), is a logical hypothesis for the observed benefit
of these drugs in canine and human patients suffering
with pemphigoid diseases, although the mode of action
in dogs remains to be elucidated.23–25
Our data indicated that oral glucocorticoid monotherapy
was the most frequent treatment regimen that failed to
induce CR. Indeed, most dogs reported in this study and
in the previous review received a combination therapy
including two or more immunosuppressants.2 Although
CR was achieved in more than 90% of dogs in this study,
a high rate of a disease relapse was observed. The relaps-
ing nature of this disease should be considered when dis-
cussing the prognosis and a long-term treatment plan
with the owner.
Microscopic findings in this study were similar to those
reported previously for canine MMP.1,2 Subepidermal
clefts, an inclusion criterion, were empty or ruptured
© 2016 ESVD and ACVD, Veterinary Dermatology, 27, 376–e94. 381
Canine mucous membrane pemphigoid
more often than filled with inflammatory cells. Ulcers
were common. Dermal inflammation often contained
eosinophils, which is also described in canine epidermoly-
sis bullosa acquisita (EBA) and BP,11,26 but their numbers
were usually low in the MMP. Although neutrophils and
eosinophils were common in the dermis, inflammation
targeted the BMZ in only few cases, where it overlapped
with the inflammatory patterns described for canine
EBA.11 Much of the moderate-to-marked inflammation in
the dermis and submucosa was considered secondary
and it was likely attributable to bacterial infection, ulcers
and/or a chronic generic response of mucosal or mucocu-
taneous tissue to injury; this was often seen as a lympho-
plasmacytic (lichenoid) band pattern. These nonspecific
inflammatory features could potentially complicate a his-
tological diagnosis.
Occasional basal keratinocyte apoptosis and pigmen-
tary incontinence were observed and were considered
nonspecific, as both can be seen with other subepider-
mal blistering diseases11 and with injured hyperplastic
epidermis or mucosa generically. Additionally, the occa-
sional keratinocyte apoptosis in AISBDs could also be
the result of anoikis, a form of apoptosis triggered by a
loss of the cell attachment to the appropriate matrix.27
Basal cell apoptosis in combination with a generic muco-
sal lichenoid inflammatory pattern might lead to a misdi-
agnosis of mucocutaneous lupus erythematosus
(MCLE), which shares clinical features with MMP includ-
ing a propensity to form mucocutaneous ulcers and a
breed predisposition for the German shepherd dog.
Mucocutaneous lupus erythematosus, however, rarely
affects the oral cavity.28 It is possible that some dogs
develop both conditions concurrently, because we have
observed one case with good histological evidence of
both MCLE and MMP.28 Suprabasal apoptosis of ker-
atinocytes might lead to a histological misdiagnosis of
the erythema multiforme (EM) group of diseases, but
usually EM presents with more suprabasal apoptosis
than that observed in this study.29 It is recommended
that clinicians collect multiple biopsies to increase their
probability of obtaining an accurate diagnosis. Fibrosis is
a recognized clinical feature of MMP in humans and
dogs.1,4 In this study, superficial dermal or submucosal
fibrosis was seen more commonly histologically than in
previous reports of canine MMP or EBA.1,11 However,
the degree of fibrosis varied from absent to marked in
biopsies from the same dog and, by itself, fibrosis is not
expected to differentiate canine MMP from other
subepidermal clefting diseases. Furthermore, chronic
secondary bacterial infection might induce fibrosis in
some cases nonspecifically, complicating identification
of any primary fibrosing features of canine MMP.4
The presence of a continuous deposit of anti-BMZ
antibodies and/or C3 complement in the skin of
affected people is a diagnostic criterion in human
MMP.4 A similar criterion has also been suggested for
canine MMP in the past, but, because direct IF is not
commercially available, this criterion is not usually and
readily fulfilled in veterinary medicine.2 In our study, 13
dogs were available for detection of tissue-bound and/
or circulating anti-BMZ antibodies; anti-BMZ antibodies,
most frequently IgG, were detected in all dogs using
direct and/or indirect IF. Sera from 11 dogs were avail-
able for indirect IF using salt-split buccal mucosa, which
distinguishes between an autoimmune response direc-
ted against antigens localized to the epidermal (collagen
XVII, BP230, integrins) or the dermal (laminins, collagen
IV, collagen VII) side of the salt-split tissue.30,31 Canine
MMP has been shown to be immunologically heteroge-
neous, with antibodies targeting various BMZ antigens
such as collagen XVII, BP230 or laminin-3322 and,
therefore, an antibody deposit can be detected at either
the epidermal or the dermal side of the salt-split
mucosa. Consequently, although the detection of anti-
BMZ antibodies is helpful in confirming the autoimmune
nature of the syndrome and narrowing down the differ-
ential diagnoses, it is in no means specific for MMP,
because other AISBD will often exhibit similar positive
results and patterns.11,26,32 This opinion is echoed in an
editorial that emphasised the importance of the clinician
in the diagnostic process.7 Finally, anti-BMZ antibodies
and/or complement are not always detected by IF in
people and dogs affected with MMP.2,33,34 In this
study, three of 11 dogs (27%) had undetectable levels
of circulating anti-BMZ autoantibodies, a percentage
similar to that previously reported in canine MMP.2
Although the exact explanation of the negative indirect
IF in the three dogs remains unknown, it is conceivable
that these three dogs might have been treated with
immunosuppressive medications before blood collec-
tion, which could have reduced anti-BMZ autoantibodies
below the detectable level. The degradation of autoanti-
bodies over time is an alternative hypothesis.
In conclusion, canine MMP is a chronic, slowly progres-
sive, mucosal/mucocutaneous-dominant AISBD fre-
quently diagnosed in middle-aged German shepherd dogs
with histological and immunological findings similar to
those reported in a previous canine MMP meta-analysis.2
Treatment with tetracycline antibiotic and niacinamide,
often in combination with other immunosuppressive drug
(s), was found to be beneficial in more than half of these
cases. Unfortunately, the rarity of this syndrome, the low
number of dogs with reported treatment outcomes in the
literature and the retrospective nature of the reports lim-
its our ability to make definitive conclusions on the best
therapeutic approach for canine MMP.
Acknowledgements
The authors thank Barbara Atlee, Kerstin Bergvall, Dor-
othy Jordan, Rudayna Ghubash, Joel Griffies, Elizabeth
Layne, Monika Linek, Nancy Peters, Helen Power, Karen
Ross, Sandra Sargent and Stephen White for providing
the case material for this study.
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Supporting Information
Additional Supporting Information may be found in the
online version of this article.
Table S1. Drugs and dosages used in 11 dogs in which
treatment regimens were available. Text in red repre-
sents protocols that did not lead to clinical remission,
whereas those in blue represent regimens inducing clini-
cal remission.
Table S2. Drugs used in all 11 dogs that did not induce
clinical remission.
R�esum�e
Contexte – La MMP (mucous membrane pemphigoid) est une dermatite d’interface sous-�epidermique
auto-immune chronique du chien, du chat et de l’homme.
Objectifs – Le but de cette �etude �etait de d�ecrire les donn�ees cliniques, histologiques et immunologiques
et l’effet des traitements de la MMP canine.
Sujets – Seize chiens ont �et�e diagnostiqu�es avec MMP bas�e sur la pr�esence de v�esicules et/ou d’ulc�eres
pr�edominant aux jonctions cutan�eo-muqueuses, avec confirmation histologique de clivage sous-�epidermi-
que et une apparition des l�esions apr�es 6 mois.
R�esultats – Six des 16 chiens (38%) �etaient des Bergers allemands ou leurs crois�es. L’age moyen de l’ap-
parition de la maladie �etait sup�erieur �a 6 ans (�ecart : 1-10 ans). Au moment de la pr�esentation, les chiens
pr�esentaient des �erosions et des ulc�eres des r�egions orale (11 sur 16; 69%), nasale (neuf sur 16; 56%),
© 2016 ESVD and ACVD, Veterinary Dermatology, 27, 376–e94. 383
Canine mucous membrane pemphigoid
p�erio-occulaire (8 sur 16; 50%) et g�enitale (sic sur 16; 38%).Les l�esions des zones velues �etaient moins
fr�equentes (six sur 16; 38%) et impliquaient principalement les faces concaves des pavillons auriculaires.
Les informations sur les effets des traitements �etaient disponibles pour 11 chiens (69%). Une r�emission
compl�ete (CR) des l�esions a �et�e obtenue pour 10 des 11 chiens (91%). Le temps moyen de CR �etait 33
semaines (�ecart : 6-64 semaines). Les protocoles de traitement variaient largement mais six des 10 chiens
(60%) ont rec�u une combinaison de t�etracycline et niacinamide seul ou avec une autre mol�ecule au
moment de la CR. Quarante pourcents des chiens ayant atteint une CR pr�esentaient une r�ecidive �a la
baisse de dose des traitements.
Conclusions et importance clinique – La MMP canine est une maladie chronique et r�ecidivante n�ecessi-
tant un traitement au long-court. Un traitement combin�e est souvent n�ecessaire pour atteindre une CR.
Resumen
Introducci�on – el penfigoide de membranas mucosas (MMP) es una enfermedad cr�onica, autoinmune
vesicular de perros, gatos y humanos.
Objetivos – el objetivo de este estudio fue describir las caracter�ısticas cl�ınicas, histol�ogicas e inmunol�ogi-
cas y resultados de tratamiento de casos de MMP canino.
Animales – 16 perros fueron diagnosticados con MMP basado en la presencia de ves�ıculas y/o ulceraci�on
predominantemente en mucosas o uniones mucocut�aneas, confirmaci�on histol�ogica de separaci�on subepi-
dermal y edad de aparici�on en animales mayores de 6 meses.
Resultados – seis de 16 perros fueron Pastores Alemanes o sus cruces. La edad media de aparici�on fue
de 6 a~nos (rango: 1-10 a~nos). Al momento de la presentaci�on, los perros presentaban erosiones y �ulceras
en la cavidad oral (11 de 16; 69%), regi�on nasal (9 de 16; 56%), regi�on periocular (8 de 16; 50%) y regi�on
genital (6 de 16; 38%). Las lesiones de la piel fueron menos frecuentes (6 de 16; 38%) y afectaban princi-
palmente a la parte c�oncava de pabellones auriculares. Informaci�on acerca del resultado del tratamiento
estaba disponible en casos (69%). Se obtuvo resoluci�on total de las lesiones (CR) en 10 de 11 perros
(91%). La duraci�on media para CR fue de 33 semanas (rango: 6-64 semanas). Los reg�ımenes de trata-
miento variaron ampliamente pero seis de 10 perros (60%) recibieron una combinaci�on de tetraciclina y nia-
cinamida solas o con otro f�armaco hasta la CR. 40% de los perros con CR presentaron recidiva tras reducir
la dosis de medicamentos.
Conclusi�on e importancia cl�ınica – el MMP canino es una enfermedad cr�onica recidivante que requiere
tratamiento a largo plazo. La terapia combinada es a menudo necesaria para obtener CR.
Zusammenfassung
Hintergrund – Das Schleimhautpemphigoid (MMP) ist eine chronische autoimmune subepidermale bla-
senbildende Erkrankung bei Hunden, Katzen und beim Menschen.
Ziele – Das Ziel dieser Studie war eine Beschreibung der klinischen, histologischen und immunologischen
Charakteristika und der Behandlungsergebnisse des MMP des Hundes.
Tiere – Sechzehn Hunde wurden mit MMP diagnostiziert, die Diagnose basierte auf Bl€aschenbildung, die
auf der Schleimhaut oder an den €Uberg€angen der Haut in die Schleimhaut auftrat und/oder Ulzerierung, die
histologische Best€atigung von subepidermaler Spaltenbildung und ein Auftreten der Erkrankung bei einem
Lebensalter von mehr als 6 Monaten.
Ergebnisse – Sechs von 16 Hunden (38%) waren Deutsche Sch€aferhunde und ihre Mischlinge. Das med-
iane Lebensalter beim Auftreten der Erkrankung lag bei 6 Jahren (Spanne: 1-10 Jahre). Zum Zeitpunkt der
Vorstellung zeigten die Hunde Erosionen und Ulzera in der Maulh€ohle (11 von 16; 69%), der Nase (neun
von 16; 56%), periokul€ar (acht von 16; 50%) und in der Genitalregion (sechs von 16; 38%). Die Ver€anderun-
gen in der behaarten Haut waren weniger h€aufig (sechs von 16; 38%) und betrafen haupts€achlich die kon-
kaven Oberfl€achen der Pinnae. Eine Information bzgl dem Therapieerfolg gab es f€ur 11 Hunde (69%). Eine
vollst€andige Remission (CR) der Ver€anderungen wurde bei 10 von 11 Hunden erzielt (91%). Die mediane
Zeit bis zur CR betrug 33 Wochen (Spanne: 6-64 Wochen). Die Behandlungsregimes variierten stark, aber
sechs von 10 (60%) Hunden erhielten zum Zeitpunkt der CR eine Kombination aus Tetrazyklin und Niacina-
mid alleine, oder mit einem anderen Medikament zusammen. Vierzig Prozent der Hunde bei denen eine
CR auftrat, zeigten bei Dosisreduzierung ein Wiederauftreten der Ver€anderungen.
Schlussfolgerungen und klinische Bedeutung – Das MMP des Hundes ist eine chronische wiederkeh-
rende Erkrankung, die einer Langzeittherapie bedarf. Eine Kombinationstherapie ist h€aufig n€otig, um eine
CR zu erzielen.
要約
背景 – 粘膜類天疱瘡(MMP)はイヌやネコ、ヒトの慢性自己免疫性表皮下水疱疾患である。目的 – この研究の目的はイヌのMMPの臨床的特徴、組織学的特徴、免疫学的特徴、および治療成績を解説することである。供与動物 – 粘膜あるいは粘膜皮膚に明らかな水疱および/あるいは潰瘍が存在すること、組織学的に表皮下に裂隙
が認められること、および発症年齢が生後6ヶ月以降であることを元に16頭のイヌをMMPと診断した。
Tham et al.
© 2016 ESVD and ACVD, Veterinary Dermatology, 27, 376–e94.e93
結果 – 16頭中6頭(38%)はジャーマン・シェパード犬とそれらの交雑種であった。発症平均年齢は6歳であった(範囲:1-10歳)。イヌは初診時に、糜爛や潰瘍が口腔内(16頭中11頭;69%)、鼻(16頭中9頭;56%)、眼周囲(16頭中8頭:50%)、ならびに生殖器周囲(16頭中6頭:38%)で認められた。有毛部の皮膚病変はより頻度が低く(16頭中6頭:38%)、ほとんどの症例で耳介内側面に症状が存在した。治療結果に関する情報は11頭(69%)で得られた。病
変の完全寛解(CR)が11頭中10頭(91%)のイヌで得られた。CRまでの平均期間は33週間(範囲:6-64週間)であった。治療法は様々であったが、10頭中6頭(60%)のイヌはCRの時にテトラサイクリン系抗菌剤およびニコチン酸アミドの組み合わせのみか、その他の併用薬を投与されていた。CRが得られた40%のイヌでは、薬剤の減量により症状の再
発が生じた。結論および臨床的な重要性 – イヌのMMPは長期的な治療を必要とする慢性および再発性疾患である。CRを得るために多くの場合、複数の薬剤を組み合わせた治療が必要である。
摘要
背景 – 黏膜类天疱疮(MMP)是犬、猫以及人的一种慢性、免疫性、表皮下水疱性疾病。目的 – 这项研究的目的为描述犬MMP的临床表现、组织学和免疫学特征以及治疗方案。动物 – 诊断为MMP的16只犬,其组织学特征主要为黏膜或黏膜皮肤结合处以水疱和/或溃疡,表皮下开裂,发病年龄大于6月龄。结果– 16只犬中的6只(38%)为德国牧羊犬或其杂交犬。该病的中值发病年龄为6岁(范围:1-10岁)。犬只口腔
(16只中的11只; 69%)、鼻部(16只中的9只; 56%)、眼周(16只8只中的b; 50%)和生殖器(16只中的6只; 38%)等位置出现糜烂和溃疡。有毛区域病变较少出现(16只中的6只; 38%),包括耳廓凹面。11只犬(69%)治疗有效。11只犬中的10只犬,其症状达到完全缓解(CR)。完全缓解的中值时间为33周(范围:6-64周)。治疗方案多样化,但是10只犬中的6只 (60%)在中值时间内接受了四环素、烟酰胺或另加一种药物的联合治疗方案。随着药物
剂量的降低,40%的犬症状出现复发。总结和临床意义 – 犬MMP是一种慢性、复发性疾病,需要长期治疗。该病常常需要联合治疗以达到完全缓
解。
Canine mucous membrane pemphigoid
© 2016 ESVD and ACVD, Veterinary Dermatology, 27, 376–e94. e94