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: pbiziko@ncsu.edu

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 (vetderm@lists.ncsu.edu) 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