19 Pemphigoid in Domestic Animals

Danny W. Scott, DVM

From the Department Pemphigoid (from the Greek “resembling pemphigus”) has been of Clinical Sciences, recognized in humans for many years. The occurence of pem- New York State Col- phigoid in domestic animals is a much more recent observation. In lege of Veterinary the dog, bullous pemphigoid was first documented in 1978.’ Equine Medicine, Cornell bullous pemphigoid was originally reported in 1981.2 The purpose University, Ithaca, of this article is to review pemphigoid in domestic animals, com- New York pare the disease with its human counterpart, and alert the physi-

cian to an exciting area for comparative dermatologic research.

Clinical Features

Bullous pemphigoid has been recognized in dogsi+ and horses.2y21 Affected dogs have ranged from 3 months to 10 years of age with no sex predilection. Collies appear to be a predilected breed.5~11)16-‘8Of the 32 cases of canine bullous pemphigoid detailed in the veterinary literature, seven (21.9%) were Collies and four (12.5%) were Doberman Pinschers. The two reported cases of equine bullous pemphigoid have occurred in Quarter Horse mares, 5 and 14 years of age.2r21 Neutering has no apparent effect on the development of the disease.

In the dog, bullous pemphigoid is a vesiculobullous, ulcerative disorder that may affect the oral cavity, mucocutaneous junctions (lips, nostrils, eyelids, prepuce, vulva, anus), skin, or any combina- tion thereof. About 80% of the dogs have oral cavity lesions at the time of diagnosis, and oral cavity ulceration may be the initial clinical sign (Figs. 1 and 2). Cutaneous lesions occur most commonly in the axillae and groin (Figs. 3 and 4). Paronychia, onychomadesis, or footpad ulceration may be seen. An insidious, chronic, clinically benign form of cutaneous bullous pemphigoid (lesions confined to axillae, groin, or isolated mucocutaneous areas such as anus and prepuce) is occasionally recognized in dogs (Figs. 5 and 6). How- ever, most cases are more severe and widespread. In the horse, bullous pemphigoid is a vesiculobullous, ulcerative disorder of the oral cavity, esophagus, mucocutaneous junctions, and skin (Figs. ‘7 and 8).

Owing to the thinness of canine and equine epidermis, vesicles and bullae are fragile and transient. Thus, clinical lesions usually include ulcers bordered by epidermal collarettes. The pseudo-

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Nikolsky signZ2 may be present. Pain and pruritus are variable, and secondary pyo- derma is common. Severely affected animals may be febrile, anorectic, and depressed, and may have peripheral lymphadenopathy.

Clinical variants of pemphigoid described in humans-cicatricial pemphigoid (muco- sal and Brunsting-Perry types), pemphigoid vegetans, vesicular pemphigoid (pemphi- goid herpetiformis), pemphigoid nodularis. and erythrodermic bullous pemphigoid- have not been reported in domestic ani- mals.23-3Z

Results of routine laboratory determina- tions (hemogram, serum chemistries, uri- nalysis, serum protein electrophoresis) are nondiagnostic, often revealing mild-to-mod- erate leukocytosis and neutrophilia, mild nonregenerative anemia, mild hypoalbumi- nemia, and mild-to-moderate elevations of (~2-, p-, and -,+globulins. Although peripheral blood eosinophilia has been reported in up to 50% of human patients with bullous pem- phigoid,33 this is rare in domestic animals.

Diagnosis

In domestic animals, the differential diag- nosis of bullous pemphigoid includes pem- phigus vulgaris, systemic lupus erythema- tosus, toxic epidermal necrolysis, erythema multiforme, mycosis fungoides, candidiasis, and the numerous causes of ulcerative stoma- titis.“~*7~34-37 The definitive diagnosis of bul- lous pemphigoid is based on history, phys- ical examination, skin or mucosal biopsy, and immunofluorescence testing (Table 1).

Biopsy may be diagnostic or strongly sup- portive. Intact vesicles or bullae are essen- tia1.4~5~1~-13~‘7 Because these lesions are so fragile and transient, it may be necessary to

hospitalize the animal so that it can be care- fully scrutinized every 2-4 hours for the presence of primary lesions. Multiple biop- sies and serial sections will greatly increase the likelihood of demonstrating diagnostic histologic changes.

Bullous pemphigoid is characterized by sub- epidermal cleft and vesicle formation (Figs. 9 and 10).2j5911-13r17 Sections stained with PAS show the basement membrane zone attached to the dermis at the floor of the blister. Subepid- ermal vacuolar alteration appears to be the earliest prevesicular histologic finding(Figs. 11 and 12). As is the case in humans,31~38~3g the inflammatory infiltrate in canine and equine bullous pemphigoid varies from mild to marked. A lichenoid cellular infiltrate is occasionally seen.11~17~40 Contrary to the situation in hu- rnans,31,38@+1!42 significant tissue eosinophilia and “eosinophilic spongiosis” are rarely pre- sent in dogs and horses.

Electron microscopic examinations of hu- man and canine bullous pemphigoid lesions have revealed smudging, thickening, and inter- ruption of the basement membrane, with sepa- ration occurring between the basal cell mem- brane and the basal lamina (the lamina lucida). 11,17,31,38

Direct immunofluorescence testing can be reliably performed on quick-frozen tissues or samples preserved in Michel’s fixa- tive.4+y17+)y43-46 Diffuse deposition of immuno- globulin (usually IgG) and complement along the basement membrane zone is usually seen (Fig. 13).114~5~9111-15,1g,30,31 Occasionally, IgM or IgA is the only immunoglobulin detected, or C3 is the only immunoreactant detected, as is the case in hurnans.ll~l2,17~30-32,47,48 It is important to sample intact vesicles and bullae and perile- sional tissue.

Great caution is warranted when assessing the significance of IgM deposits in canine

TABLE 1. lmmunopathology in Canine Bullous Pemphigoid

Direct Immunofluores-

Number of cence Testing

Indirect Immunofluo- Antinuclear Lupus Erythema-

Patients IgG IgA IgM C3 rescence Testing Antibody* tosus Cell Test

7 4 4 2 5 1 (1:2048) 0 0

*Normal dogs in this laboratory will have an ANA of 0.

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skin. IgM may be found deposited at the basement membrane zone of normal dog skin, especially when nose or footpad are examined (Fig. 14).49-51 Similar findings have been reported for normal human skin.52 In addition, concurrent or recent systemic glucocorticoid therapy may cause false-nega- tive test results, even in the face of active lesions.4~16,53~54

Indirect immunofluorescence testing is not commonly positive in canine bullous pem- phigoid (5 of the 32 reported cases, or 15.7%).1~4~5*9-17~19 This is in contrast to the situation in humans, wherein about 70% of bullous pemphigoid patients have positive resu1ts.29-31~4~~55 Both reported cases of equine bullous pemphigoid were positive on indirect immunofluorescence testing.zyz1

The reason for the low number of positive indirect immunofluorescence test results in dogs as compared to humans is not known. It may be that all pemphigoid antibody in dogs is usually bound to substrate in wivo or is bound in circulating immune complexes.@j+7@ In addition, detection of pemphigoid anti- bodies can be fraught with difficulties (tech- nical problems with procedures, prozones, and substrate selection; immune complexes; multiple serum samples may be re- quired.30,64,55,58-61 In no species does the pem- phigoid antibody titer correlate well with the extent or severity of clinical disease or with prognosis.

Pemphigoid-like antibodies have been rare- ly reported in humans, especially burn pa- tients.3°,31y56 Pilot studies in dogs and horses with various dermatologic and non- dermatologic diseases, and in animals with no disease, failed to detect pemphigoid-like antibodies.49756 Thus, pemphigoid-like anti- bodies would appear to be a rare cause of false-positive test results in indirect immuno- fluorescence testing.

Clinical Management

The prognosis for canine bullous pemphigoid appears to vary with the extent of dis- ease.1~3~4+13~17 The natural course of untreated cases is unclear. Veterinarians have long rec-

ognized refractory mucocutaneous ulcerative disorders that have resulted in the death or euthanasiaof affected animals. Retrospectively, many of those animals may have had bullous pemphigoid. Based on the small number of cases documented in veterinary literature, (1) generalized canine and equine bullous pem- phigoid appear to be severe diseases, often fatal (septicemia) unless treated; and (2) localized cutaneous canine bullous pemphigoid is usu- ally a benign disorder, rarely producing sys- temic signs.

Therapy of canine bullous pemphigoid is often difficult, requiring large doses of sys- temic glucocorticoids, with or without other potent immunomodulating drugs.4,11-13917 Side effects are common, varying from mild to severe, and close physical and hematologic monitoring of the patient is critical. Addition- ally, therapy usually must be maintained for prolonged periods of time, if not for life. Thus, the therapeutic regimen must be individual- ized for each patient, and owner education is essential.

Large doses of systemic glucocorticoids (l-3 mg/kg prednisolone or prednisone, given orally BID) are often listed as the initial treatment of choice for pemphigoid.3,4,11-13,17129,31,32,47,62-64 In

many instances, however, glucocorticoid ther- apy is unsuccessful, or intolerable side effects develop. 4,1(t17,29,31,32,47,65,66

Mild cases of canine bullous pemphigoid may be managed with relatively low doses of systemic glucocorticoids (1 mg/kg prednisone or prednisolone given orally BID), and therapy may occasionally even be terminated.1~3~4~7 Most cases, however, require aggressive chemother- apy.lO-l’ In one study of nine dogs with bullous pemphigoidl2 the following observations were made: (1) 1 mg/kg rednisolone given orally BID was ineffective for controlling the disease, and (2) 3 mg/kg prednisolone given orally BID was effective. At the larger dose, however, two of the nine dogs were euthanized because of unac- ceptable side effects, and another two died after 7-10 days of therapy (acute pancreatitis). Thus, systemic glucocorticoids were unsatis- factory for treatment in four of nine dogs (44%).

When systemic glucocorticoids are unsatis- factory, the addition or substitution of other

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FIG. 1. Severe ulceration of the oral cavity in a dog with bullous pemphigoid.

FIG. 2. Ulceration of the lips and tongue in a dog with bullous pemphigoid.

FIG. 3. Annularand serpiginous ulcers on the abdomen and groin ofadog with bullous pemphigoid.

FIG. 4. Scrotal erythema and ulceration in a dog with bullous pemphigoid.

FIG. 5. Perianal ulceration in a dog with bul- lous pemphigoid.

FIG. 6. Preputial ulceration in a dog with bullous pemphigoid.

FIG. 7. Severe ulceration of the oral cavity in a horse with bullous pemphigoid. (From Man- ning TO, et al. Pemphigus-pemphigoid in a horse. Equine Pratt. 1961:5(3): 36-44.)

FIG. 6. Vulvar ulceration in a horse with bul- lous pemphigoid. (From Manning, TO, et al. Pemphigus-pemphigoid in a horse. Equine Pratt. 1961:5(3):36-44.)

FIG. 6 (facing page). Subepidermal vesicle in adog with bullous pemphigoid. Hematoxylin and eosin stain, original magnification, X75. (From Scott DW, Lewis RM. Pemphigus and pemphigoid in dog and man: comparative as- pects. J Am Acad Dermatol. 1961;5:146-167.)

FIG. 10 (facing page). Subepidermal vesicle in a horse with bullous pem- phigoid. Hematoxylin and eosin stain, original magnification, X75. (From Manning TO, et al. Pemphigus-pemphigoid in a horse. Equine Pratt. 1961:5(3):36-44.)

FIG. 11 (facing page). Subepidermal vacuolaralteration and lichenoid cell-

January-March 1987 Volume 5 Number 1 Pemphigoid in Domestic Animals 159

ular infiltration in a dog with bullous pemphigoid. Hematoxylin and eosin stain, original magnification, X75. (From Muller GH, Kirk RW, Scott DW, et al. Small Animal Dermatology III. Philadelphia: WB Saunders, 1983:466.)

FIG. 12. Subepidermal vacuolar alteration in a dog with bullous pemphigoid. Hematoxylin and eosin stain, original magnification, X300. (From Scott DW, Lewis RM. Pemphigus and pemphigoid in dog and man: comparative aspects. J Am Acad Dermatol. 1981;5:148-167.)

FIG. 13. Direct immunofluorescence testing using fluorescein-labelled rabbit anticanine IgG. Host IgG is deposited at the basement membrane zone in a dog with bullouspemphigoid original magnification, X300. (From Scott DW, et al. Observations on the immuno- pathology and therapy of canine pemphigus and pemphigoid. J Am Vet Med Assoc. 1982; 18648-52.)

FIG. 14. Direct immunofluorescence testing using fluorescein-labelled rabbit anticanine IgM. Host IgM is deposited at the basement membrane zone in the nose of a normal dog (X259). (From Scott, DW, et al. Pitfalls in immunofluorescence testing in dermatol- ogy. II. Pemphigus-like antibodies in the cat, and direct immunofluorescence testing of normal dog nose and lip. Cornell Vet. 1983;73:275-279.)

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immunomodulating drugs may allow signifi- cant reduction or termination of glucocorticoid dosage, and superior patient manage- ment,% IO-139 15-17,29,31,32,47,66-70 Drugs that are often

useful include azathioprine (2.2 mg/kg orally SID or every 48 hours), chlorambucil (0.2 mg/kg orally every 48 hours), cyclophospham- ide (50 mg/m2 BSA every 48 hours), Gmercap- topurine (50 mg/mz BSA SID or every 48 hours), dapsone (1 mg/kg orally TID), or auro- thioglucose.4,10-13,15-17,29,31,32,47,67-70

Chrysotherapy (gold compounds) has been effective for the management of canine bullous pemphigoid.13~15~17~71 Aurothioglucose is admin- istered intramuscularly in two “test doses” one week apart: 1 and 2 mg for dogs weighing less than 10 kg, and 5 and 10 mg for dogs over 10 kg. Dogs are then given 1 mg/kg weekly until a clinical response is seen (6-12 weeks). Systemic glucocorticoids may be used concurrently with chrysotherapy during the 6-12-week clinical “lag phase” if needed. Injections of aurothio- glucose are then given every 2 weeks for a month, and then monthly. Adverse reactions to chrysotherapy are, thus far, rare in animals. Transient thrombocytopenia and bleeding were reported in one dog.15

Because the cutaneous lesions of human bullous pemphigoid have been induced by ultraviolet irradiation,72y73 and the lesions of canine bullous pemphigoid have been re- ported to worsen with exposure to sunlight,16 it may be prudent to avoid direct exposure to sunlight between 8:00 AM and 5:00 PM.

Conclusion

The “recent advent” of pemphigoid in do- mestic animals has provided an exciting new area for comparative dermatologic research. The animal and human forms of bullous pemphigoid appear to possess many clinico- pathologic similarities, and the veterinary and physician dermatologist would do well to keep abreast of advances in both fields.

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Address for correspondence: Danny W. Scott, D.V.M., Department of Clinical Sciences, New York State College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.