Subepidermal Blistering 2008: Canine Pemphigoid-Like Diseases
ACVIM 2008
Danny W. Scott, DVM, DACVD
Ithaca, NY, USA

Bullous pemphigoid was first reported in a dog in 1978.1 Reviews of the clinical signs, diagnosis, and treatment began to appear in the 1980s.2,3 Due to the remarkable advances in immunopathology and molecular biology over the last decade, it is clear that what we once called "bullous pemphigoid" is actually 5 different diseases.4-6

Pathogenesis

Pemphigoid diseases are characterized by the presence of autoantibodies that target various structures that are crucial to the integrity of the basement membrane zone of the epidermis and oral mucosa.4-6 Most cases of pemphigoid diseases in dogs are spontaneous and idiopathic. Genetic predisposition is suspected (e.g., breeds over-represented, familial occurrence),4,6 photoaggravation (thus, exacerbation in sunny weather) may occur,4 and drug-induced cases are reported.4 Lesion severity and locations are, at least in part, determined by the autoantigens targeted and the regional expression of these autoantigens.4,6

Collagen XVII (bullous pemphigoid antigen 2; 180 kDA) is the major autoantigen in canine and human bullous pemphigoid.4,6,7 Mucous membrane ("cicatricial") pemphigoid is an immunologically heterogenous disease with autoantibodies targeting collagen XVII, laminin 5/6, and integrin α-6/β-4.4,6,8 Linear IgA bullous dermatosis is characterized by autoantibodies that target the processed extracellular segment of collagen XVII (LAD 1; 120 kDa).4,6,9 The aminoterminal noncollagenous domain of collagen VII is the major autoantigen in epidermolysis bullosa acquisita.4,6,10 The autoantigen targeted in bullous systemic lupus erythematosus is collagen VII.4,6,11

Diagnostic Testing

Clinical (vesicles, bullae, ulcers) and histopathological findings (subepidermal cleft and vesicle formation) frequently overlap in these diseases. Routine immunohistochemical and immunofluorescence testing procedures are fraught with false-positive results, and do not separate these entities.4-6 Immunoblotting, immunoprecipitation, and specific ELISA technologies are necessary to demonstrate the specific autoantigens being targeted.4-6 Such methodologies are currently research tools.

Bullous Pemphigoid (BP)

BP accounted for 12% of the dogs with autoimmune subepidermal blistering diseases in one series.6 There is no sex predilection, but dachshunds may be over-represented. The median age of onset is 5 years (range 9 months to 7 years).

Erythematous plaques and tense vesicles or bullae result in ulcers. More-or-less symmetrical lesions first appear on the head, pinnae, or trunk. Oral and mucocutaneous junctions (especially lips) can be involved but paw pads are rarely affected. Patients are typically otherwise healthy.

The diagnosis of BP is confirmed by histopathological and immunopathological findings.5,6 Subepidermal vesicles are usually associated with eosinophilic and neutrophilic inflammation. Immunofluorescence testing frequently demonstrates epithelium-fixed (direct method) or, less commonly, circulating (indirect method) IgG autoantibodies binding to the basement membrane zone.5,6 ELISA or immunoblotting procedures detect circulating autoantibodies targeting collagen XVII.5,6

Mucous Membrane Pemphigoid (MMP)

MMP accounted for 53% of the dogs with autoimmune subepidermal blistering diseases in one series.6 There is no apparent sex predilection, but German shepherds and Siberian huskies may be over-represented. The median age of onset is 5 years (range 1.5 to 15 years).

Tense vesicles or bullae progress to ulcers. More-or-less symmetrical lesions first appear in the oral cavity, on or around the nose, inside the ears, or in or around the genitalia.8 Lesions are uncommonly present on paw pads and haired skin distant from mucocutaneous junctions. Affected dogs are usually otherwise healthy.

The diagnosis of MMP is confirmed by histopathological findings.5,6 Subepidermal vesicles may be noninflammatory or associated with eosinophils, neutrophils, or mononuclear cells. Immunofluorescence testing frequently demonstrates epithelium-fixed (direct method) or, less commonly, circulating (indirect method) IgG autoantibodies binding the basement membrane zone.5,6,8 ELISA or immunoblotting procedures detect circulating autoantibodies targeting collagen XVII or laminin 5.6,8

Epidermolysis Bullosa Acquisita (EBA)

EBA accounted for 20% of the dogs with autoimmune subepidermal blistering diseases in one series.6 Males (2:1) and Great Danes appear to be over-represented. The median age of onset is one year (range 6 months to 8 years).

Erythematous and urticarial patches progress to tense clear or hemorrhagic vesicles, then ulcers. More-or-less symmetrical lesions are seen on the nasal planum, pinnae, axillae, groin, and paw pads.5,6,10 Oral mucosal sloughing is seen in all dogs. Affected dogs are usually ill, having lethargy, depression, and pyrexia. Rarely, dogs with EBA may have a localized phenotype (head, ears) and no systemic illness.6,12

The diagnosis of EBA is confirmed by histopathological and immunopathological findings.5,6 Subepidermal vesicles are associated with neutrophilic infiltrates and neutrophilic subepithelial microabscesses. Immunofluorescence testing frequently demonstrates epithelium-fixed (direct method) or, less commonly, circulating (indirect method) IgG autoantibodies binding the basement membrane zone.5,6 ELISA or immunoblotting procedures detect circulating autoantibodies targeting collagen VII.6,10

Linear IgA Bullous Dermatosis (LIBD)

LIBD accounted for 4% of the dogs with autoimmune subepidermal blistering diseases in one series.5 There are too few reported cases to allow statements on age, breed, and sex.

Tense vesicles and bullae progress to ulcers. Clinical signs are similar to those recorded for EBA.5,9

The diagnosis of LIBD is confirmed by histopathological and immunopathological findings.5 Subepidermal vesicles are noninflammatory or associated with neutrophilic infiltrates. Immunofluorescence testing demonstrates tissue-fixed or circulating IgA autoantibodies binding the basement membrane zone.5,9 ELISA or immunoblotting procedures detect circulating autoantibodies targeting the processed extracellular segment of collagen XVII.5,9

Management

The optimal therapy (if such exists) for canine pemphigoid-like diseases has not been determined. The following observations are useful.5,6

1.  BP may respond to prednisolone (2 mg/kg/day initially) with or without azathioprine (2.5 mg/kg/day initially), or tetracycline and niacinamide (see Pemphigus).5,6

2.  MMP may respond to prednisolone (2 to 4 mg/kg/day initially) with or without azathioprine (2.5 mg/kg/day initially) or chlorambucil (0.2 mg/kg/day initially), or tetracycline and niacinamide (see Pemphigus), or dapsone (see Pemphigus).5,6

3.  EBA is more difficult to treat than BP or MMP.5,6 Only 50% of the dogs respond to prednisolone with or without azathioprine.

4.  LIBD is also difficult to treat.5,6 Dapsone and colchicine are often useful in humans with LIBD.

References

1.  Kunkle G, et al. J Am Anim Hosp Assoc 1978;14:52.

2.  Scott DW, et al. J Am Vet Med Assoc 1982;180:48.

3.  Scott DW. Clin Dermatol 19897;5:155.

4.  Scott DW, et al. Muller & Kirk's Small Animal Dermatology VI 2001:694.

5.  Olivry T, et al. Clin Dermatol 2001;19:750.

6.  Chan LS. Animal Models of Human Inflammatory Skin Diseases 2004:201.

7.  Iwasaki T, et al. Vet Pathol 1995;32:387.

8.  Olivry T, et al. J Autoimmunity 2001;16:411.

9.  Olivry T, et al. Vet Pathol 2000;37:302.

10. Olivry T, et al. Vet Dermatol 1998;8:401.

11. Olivry T, et al. Vet Rec 1999;145:165.

12. Olivry T, et al. Vet Rec 2000;146:193.

Speaker Information
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Danny Scott, DVM, DACVD
Cornell University
Ithaca, NY


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