Pemphigus 2008: Pathogenesis, Presentation, & Management
ACVIM 2008
Danny W. Scott, DVM, DACVD
Ithaca, NY, USA

Pemphigus diseases were first documented in dogs in the 1970s: pemphigus vulgaris in 1975,1 pemphigus foliaceus in 1977.2 Pemphigus erythematosus and paraneoplastic pemphigus were first reported in 1980 and 1998, respectively.3,4 Reviews of the clinical signs, diagnosis, and treatment of these diseases began to appear in the 1980s.5-8 Remarkable advances in the understanding of the pathogenesis, diagnosis, and management of canine pemphigus diseases have been made in the last decade.9,11

Pathogenesis

Pemphigus diseases are characterized by the presence of autoantibodies that target various structures that are crucial to the integrity of keratinocyte cell-to-cell adhesion.9,10 Most cases of pemphigus in dogs are spontaneous and idiopathic. Genetic predisposition is suspected (e.g., breeds over-represented, familial occurrence),9,10 photoaggravation (thus, exacerbation in sunny weather) and drug-induced disease are well-known,9-11 and even diet may play a role.9 Lesion severity and locations are, at least in part, determined by the autoantigens targeted and the regional expressions of these autoantigens.9,10

Desmoglein 3 (130 kDa) is a major autoantigen in canine and human pemphigus vulgaris.10,12 Dogs with mucocutaneous and cutaneous progression also have circulating IgG autoantibodies against desmoglein 1, perhaps as a result of epitope spreading.9,10 Dogs and humans with pemphigus vulgaris may also have circulating autoantibodies against other keratinocyte constituents (e.g., envoplakin, periplakin, cholinergic receptors), but these are presently of undetermined significance.10,13-15

Desmoglein 1 (160 kDa) is the major autoantigen in humans with pemphigus foliaceus.10 However, in dogs, desmoglein 1 appears to be a minor autoantigen.11,16 In fact, there appears to be considerable immunological heterogeneity in canine pemphigus foliaceus.11,17

Paraneoplastic pemphigus is characterized by a unique assembly of immunopathological findings: (1) epithelium-fixed IgG autoantibodies binding keratinocyte cell membrane, (2) circulating IgG autoantibodies binding rodent urinary bladder, and (3) circulating IgG autoantibodies against desmoplakins 1 and 2, envoplakin, periplakin, and desmoglein 3.4,9

Diagnostic Testing

Histopathological findings are the cornerstone of diagnosis for the practicing veterinarian.9 Immunohistochemical and immunofluorescence testing procedures are fraught with false-positive and, to a lesser extent, false-negative results.8-11 Immunoblotting, immunoprecipitation, and specific ELISA technologies are necessary to demonstrate the specific autoantigens being targeted.9-11 Such methodologies are currently research tools.

Pemphigus Vulgaris (PV)

PV is the most severe and one of the rarest of the canine pemphigus diseases discussed herein. It represented 0.12% of the dogs with skin disease examined at a university clinic.8 Because of a lack of reference population, a breed predisposition cannot be established. However, German shepherd dogs and collies appear to be over-represented among all dogs reported in the literature.10 The median age of onset is 6 years (range 6 months to 14 years). There is no apparent sex predilection.

Fragile and transient vesicles and bullae are rapidly ruptured, resulting in erosions and ulcers. In "classical" PV, more-or-less symmetrical lesions are first seen on the oral mucosa and mucocutaneous junctions. The lateral surface of pinnae, nasal planum, clawbeds, and pressure point/frictional areas (axillae, groin, bony prominences, paw pads) are commonly affected as the disease progresses. Affected dogs are often inappetent, depressed, and lethargic. Unusual "milder" or "localized" forms of canine PV include patients with lesions isolated to the bridge of the nose,10,18 nasal planum,19 or clawbeds (onychomadesis).10,18

The diagnosis of PV is confirmed by histopathological and immunopathological findings.9,10 Suprabasilar acantholysis results in clefts and vesicles within the epidermis and hair follicle infundibula. Immunofluorescence testing frequently demonstrates epithelium-fixed (direct method) or, less commonly, circulating (indirect method) IgG autoantibodies binding the cell membrane of gingival keratinocytes.10 ELISA or immunoblotting procedures detect circulating autoantibodies targeting the desmosomal cadherin desmoglein 3.10 As mucosal-predominant disease evolves into a mucocutaneous phenotype, IgG autoantibodies against desmoglein 1 (pemphigus foliaceus antigen) are also detected.9 Appropriate immunofluorescence, ELISA, and immunoblotting are generally unavailable to the practicing veterinarian.

Untreated "classical" PV is usually fatal (spontaneous death or euthanasia).8-10 "Milder" or "localized" forms have a better prognosis.

Pemphigus Foliaceus (PF)

PF is the most common form of pemphigus in dogs. It represented 0.27% of the dogs with skin disease examined at a university clinic.8 Breed risks vary from report to report, but Akitas and Chows are consistently over-represented in the United States.11 The median age of onset is 5 years (range 4 months to 16 years). There is no apparent sex predilection.

Fragile and transient pustules (rarely vesicles) are rapidly ruptured, resulting in erosions, epidermal collarettes and crusts. In "classical" PF, more-or-less symmetrical lesions are seen on the nasal planum, bridge of the nose, face, and pinnae.9-11,20-22 The paws, clawbeds, paw pads, and trunk are commonly affected as the disease progresses. Pruritus varies from absent to severe. Dogs with widespread lesions may be inappetent, depressed, and lethargic. Unusual "milder" or "localized" forms of canine PF include patients with lesions isolated to the nasal planum and/or paw pads or clawbeds.

The diagnosis of PF is confirmed by cytological, histopathological, and immunopathological findings.9,10 Direct smears from pustules and exudates reveal neutrophils (most are nondegenerate) and/or eosinophils, no microbes ("sterile"), and numerous acantholytic keratinocytes occurring singly or in clusters ("rafts"). Intragranular and/or subcorneal acantholysis results in clefts and pustules within the epidermis and hair follicle infundibula. Immunofluorescence testing frequently demonstrates epithelium-fixed (direct method) or, less commonly, circulating (indirect method) IgG autoantibodies binding the cell membrane of canine paw pad, bovine esophagus, or neonatal mouse skin keratinocytes.9,10 ELISA or immunoblotting procedures detect circulating IgG autoantibodies targeting the desmosomal cadherin desmoglein 1 in a minority of patients.10

Untreated "classical" PF is often fatal (spontaneous death or euthanasia).8,9 "Milder" or "localized" forms have a better prognosis.

Pemphigus Erythematosus (PE)

PE is the mildest form of pemphigus in dogs. It represented 0.09% of the dogs with skin disease examined at a university clinic.8 Collies and German shepherd dogs may be over-represented in the United States.8,9 There are no apparent age or sex predilections.

Fragile and transient pustules (rarely vesicles) are rapidly ruptured, resulting in erosions, epidermal collarettes, and crusts. More-or-less symmetrical lesions are seen on the nasal planum, bridge of the nose, face, and pinnae.8,9 Pruritus varies from absent to intense. Lesions typically remain localized, and affected dogs are usually otherwise healthy.

The diagnosis of PE is confirmed by cytological, histopathological, and immunopathological findings.8,9 Direct smears from pustules and exudates reveal neutrophils (most are nondegenerate) and/or eosinophils, no microbes ("sterile"), and numerous acantholytic keratinocytes occurring singly or in clusters ("rafts"). Intragranular and/or subcorneal acantholysis results in clefts and pustules within the epidermis and/or hair follicle infundibula. Immunofluorescence testing frequently demonstrates epithelium-fixed (direct method) or, less frequently, circulating (indirect method) IgG autoantibodies binding the cell membrane of keratinocytes. The direct method also frequently reveals epithelium-fixed IgG autoantibodies at the basement membrane zone. Antinuclear antibodies are often present.

Canine PE has a good prognosis.8,9

Paraneoplastic Pemphigus (PP)

Canine PP appears to be extremely rare, with only two cases documented.4,23 Dogs present with severe oral ulceration and polymorphous skin eruptions (erythema multiforme-like). Diagnosis is confirmed by histopathological (combined suprabasilar acantholysis and interface disease with pronounced keratinocyte apoptosis at all levels of the epithelium) and immunopathological (see Pathogenesis) findings, as well as discovering the associated neoplasm (thymic lymphoma, splenic sarcoma). Prognosis is grave unless the underlying neoplasia can be cured.

Management

In human medicine, etiologic and therapeutic reminders are inherent in the acronym PEMPHIGUS: PEsticides, Malignancy, Pharmaceuticals, Hormones, Infectious agents, Gastronomy, Ultraviolet radiation, and Stress.24 Veterinary medicine would be wise to remember this acronym. Addressing these factors can hasten healing, decrease required drug doses, and decrease the duration of therapy.

The optimal therapy (if such exists) for canine pemphigus has not been determined. Results of large retrospective studies indicate a survival rate of 40 to 90%.20-22,25 Sex, age, duration of disease, distribution of lesions, initial drug treatment, the use of antibiotics, and the use of gastric protectants had no effect on survival.21,22 Most dogs require long-term (life-long?) treatment.9,10,21,22,26

The following drugs have been used in various combinations for the treatment of canine pemphigus:9,11,21,22,27

1.  Topical glucocorticoids (e.g., Synotic,® betamethasone): especially PE.

2.  Topical tacrolimus (Protopic®): especially PE.

3.  Systemic glucocorticoids (prednisolone, methylprednisolone): 2-6 mg/kg/day; successful in about 50% of the cases as single therapy.

4.  Azathioprine (Imuran®): 2.5 mg/kg/day initially; steroid-sparing or solitary.

5.  Chlorambucil (Leukeran®): 0.1-0.2 mg/kg/day initially; steroid-sparing or solitary.

6.  Mycophenolate mofetil (CellCept®:) 20-40 mg/kg/day divided q8h; steroid-sparing only.

7.  Tetracycline and niacinamide: 250-500 mg q8h of each initially; steroid-sparing or stand alone (25% of cases?).

8.  Cyclosporine (Atopica,® generics): 5 mg/kg/day; steroid-sparing?, not effective alone.28

9.  Dapsone: 1 mg/kg q8h initially; steroid-sparing.

10.  Chrysotherapy (sodium aurothiomalate, Myochrysine®): 1 mg/kg weekly initially; steroid-sparing or stand alone (25% of cases?).

References

1.  Stannard AA, et al. J Am Vet Med Assoc 1975;166:575.

2.  Halliwell REW, et al. J Am Anim Hosp Assoc 1977;13:431.

3.  Scott DW, et al. J Am Anim Hosp Assoc 1980;16:815.

4.  Lemmens P, et al. Vet Dermatol 1998;9:127.

5.  Scott DW, et al. J Am Acad Dermatol 1981;5:148.

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

7.  Scott DW. Clin Dermatol 1983;1:141.

8.  Scott DW, et al. Compend Cont Educ 1987;9:423.

9.  Scott DW, et al. Muller & Kirk's Small Animal Dermatology VI 2001:667.

10. Chan LS. Animal Models of Human Inflammatory Skin Diseases 2004:261.

11. Olivry T. Vet Dermatol 2006;17:291.

12. Olivry T, et al. Exper Dermatol 2003;12:198.

13. Olivry T, et al. Vet Pathol 2000;37:496.

14. Nguyen VT, et al. Arch Dermatol 2004;140:327.

15. Lanza A, et al. J Cutan Pathol 2006;33:401.

16. Olivry T, et al. Vet Immunol 2006;l10:245.

17. Lennon EM, et al. Vet Pathol 2006;17:216.

18. Scott DW, et al. J Am Anim Hosp Assoc 1982;18:401.

19. Foster AP, et al. Vet Rec 2001;148:450.

20. Ihrke PJ, et al. J Am Vet Med Assoc 1985;186:59.

21. Mueller RS, et al. J Am Anim Hosp Assoc 2006;42:189.

22. Gomez SM, et al. J Am Vet Med Assoc 2004;224:1312.

23. Elmore SA, et al. Vet Pathol 2005;42:88.

24. Brenner S, et al. Skinmed 2003;2:163.

25. Kummel BA. Kirk's Current Veterinary Therapy XIII 1995:636.

26. Olivry T, et al. Vet Dermatol 2004;15:245.

27. Rosenkrantz WA. Vet Dermatol 2004;15:90.

28. Olivry T, et al. Vet Rec 2003;152:53.

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


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