Volume 53 | Issue 1 Article 4

1991 Pemphigus: An Autoimmune Complex in Dogs and Cats A. K. Takayama Iowa State University

D. S. Busch

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Recommended Citation Takayama, A. K. and Busch, D. S. (1991) "Pemphigus: An Autoimmune Complex in Dogs and Cats," Iowa State University Veterinarian: Vol. 53 : Iss. 1 , Article 4. Available at: https://lib.dr.iastate.edu/iowastate_veterinarian/vol53/iss1/4

This Article is brought to you for free and open access by the Journals at Iowa State University Digital Repository. It has been accepted for inclusion in Iowa State University Veterinarian by an authorized editor of Iowa State University Digital Repository. For more information, please contact [email protected]. Pemphigus: An Autoimmune Complex in Dogs and Cats

A. K. Takayama, BBA, BS, DVM* D.S. Busch, DVM**

Introduction sponse to the host cell antigen by T helper cells, (5) autoantigen modification -- modification of a The nan1e Pemphigus, derived 'from the Greek host cell antigen that renders it autoantigenic, (6) word for blister, describes a group of vesiculobull­ cross-reacting antigens -- sharing of determi­ ous diseases of the skin of dogs, cats, and hu­ nants between exogenous antigens and host cell n1ans. The pemphigus complex is an autoim­ antigens."5 In addition to these, Muller et al mune disease of the skin characterized by lesions proposes an inappropriate interleukin 2 produc­ ranging from vesiculobullous/pustular to erosive/ tion and an idiotype-anti-idiotype imbalance as ulcerative. Lesions of pemphigus are due to the well as sexual dimorphism ("with female sex binding of autoantibody to an antigen in the epi­ hormones tending to accelerate immune re­ dermal cell membrane or the glycocalyx causing sponses and male sex hormones tending to sup­ a release of an enzyme(s) resulting in disruption press responses") as mechanisms of autoim­ of intercellular attachn1ents and acantholysis. 1 mune diseases.2 The pemphigus complex is a Pemphigus produces lesions that are restricted group of disorders characterized by an inappro­ to the epidermis. More speci"fically, these lesions priate immune response. are suprabasilar, each variant being character­ Although the exact mechanism of lesions ized by location within the epidermal layer and by produced in pemphigus is not fully understood, location of lesions on the body. Muller et al have proposed a pathomechanism for lesion production which includes: "(1) the binding Pathogenesis of pemphigus antibody at the glycocalyx of ker­ atinocytes, (2) internalization of the pemphigus There are several mechanisms proposed for antibody and fusion of the antibody with intracel­ the breakdown or loss of control in self-tolerance. lular Iysosomes, and (3) resultant activation and Gorman and Werner have proposed the following release of a keratinocyte proteolytic enzyme mechanisms of autoimmune disease: "(1) poly­ ("pempbigus acantholytic factor"), which diffuses clonal B cell activation -- B cell clones are stimu­ into extracellular space and hydrolyzes the glyco­ lated by a pathogen as well as autoreactive B cell calyx" resulting in "acantholysis and blister forma­ clones resulting in the production of autoantibod­ tion within the epidermis."2 The acantholysis in ies, (2) T suppressor cell bypass -- effective T cell pemphigus has been likened to a Type II hy­ suppression is bypassed when the presence of an persensitivity reaction. There seems to be a exogenous agent on a cell surface induces a controversy remaining over whether or not com­ response to the exogenous antigen and the cell plen1ent is involved in lesion production in pem­ surface antigen, (3) T suppressor cell dysfunc­ phigus. Muller et al2 believe that "pemphigus tion-- allows expansion of autoreactive B cell and antibody-induced acantholysis is not dependent T cell clones, (4) increased T helper cell function­ on complement or inflammatory cells." However, - increases recognition and induction of a re- Jordan et al state that "complement activation by pemphigus antibodies provides an additional *Dr. Takayama is a 1990 graduate of the College mechanism for loss of epidermal cell cohesion in of Veterinary Medicine. addition to the plasminogen-plasmin system."3 It **Dr. Busch, formerly a resident in Internal Medi­ has long been known that complement (espe­ cine in the College of Veterinary Medicine at Iowa cially C3) deposits are present in pemphigus State University, is in private practice in Baltimore, lesions as has been shown through immunofluo­ Maryland. rescence staining, but their role in lesion produc-

Vol 53, No.1 15 lesion production is still not clear. Medleau et al ciency, diabetes, heavy metal poisonings, viral seemed to clear up the discrepancy best. She diseases (FeLV, feline rhinotracheitis, feline cal­ states that "complement does not appear to have icivirus), neoplasia, granuloma, pemphigus, and a primary role (in lesion production) because IgG lupus erythematosus. from C3-depleted serum can induce acantholysis in epidermal cell cultures, hO\NeVer, complement Pemphigus Vegetans may have a secondary role in that extracellular proteases released subsequent to pemphigus Pernphigus vegetans is believed to be a be­ binding may generate chemotactic fragments of nign variant of pemphigus vulgaris and has been 2 C3 or C5 which in turn could recruit polymor­ rarely reported in the dog. ,9 In humans, pem­ phonuclear granulocytes into the area."4 phigus vegetans is classified as either the Neu­ mann or the Hallopeau type. Clinically, the Neu­ Pemphigus Vulgaris mann type forms vesicles and bullae as in pem­ phigus vulgaris, but during the healing process Of the pernphigus complex, pemphigus vul­ the affected areas form verrucous vegetations. garis was first reported in 1975 and has been The Hallopeau type form pustules initially and recognized in dogs and cats. The disease does also have a papillomatous, proliferative healing not seem to have any age, breed, or sex predilec- response. 9 There are apparently no age, breed, tions. It is a vesiculobullous disease that quickly or sex predilections. Differentials for pernphigus develops into erosive/ulcerative lesions of the vegetans include: bacterial and fungal granulo­ skin, oral cavity, and mucocutaneous junctions. mas, Iymphoreticular neoplasia, mastocytoma, Muller et al2 report that "ninety percent of dogs and papilloma and fibropapilloma.2 cats with pemphigus vulgaris have oral lesions." Pemphigus vulgaris lesions, strictly limited to the Pemphigus Foliaceus skin, are rare.? In dogs, the cutaneous lesions are commonly found in the axillary and groin areas. Pemphigus foliaceus is considered the most Although this is a vesiculobullous disorder, ves­ cornmon form of pemphigus in the dog and cat. icles are very transient and fragile, thus the clinical There seems to be no sex predilection. The lesions appear as erosions and ulcers bordered disease seems to affect rrliddle-aged dogs and 2 by epidermal collarettes. ,6 The Nikolsky sign is according to a study done by Ihrke et ai, four characteristic of pemphigus and can be elicited by breeds of dogs were at a higher risk: Bearded applying finger pressure at the lateral aspect of an Collie, Akita, Newfoundland, and Schipperke. 10 erosion or to normal-appearing skin, which would Muller2adds Chow Chows, Doberman Pinschers, dislodge the epidermis from the dern1is thus cre­ and Dachshunds to the above list of breeds that ating a new erosion. This sign mayor may not be are apparently predisposed to pemphigus foli­ present and is not diagnostic fOr"pemphigus. The aceus. They often have footpad lesions charac­ disease may also have systemic effects in which terized by erythematous swelling at the pad mar­ anorexia, depression, and fever may be present. gins, cracking, and villous hypertrophy (villous In the dog, the list of differential diagnoses for hyperkeratosis or "hard pad").2,1o These footpad pemphigus vulgaris include: bullous pemphigoid, lesions often cause pain with resulting lameness. systemic lupus erythematosus, erythema rnulti­ Vesicles and bullae are transient and the animals forme, toxic epidermal necrolysis, drug eruption, are usually presented with pustules and erosions mycosis fungoides, Iymphoreticular neoplasia, bordered by epidermal collarettes. The epidermal candidiasis, and numerous causes of ulcerative collarettes with accompanying alopecia, scaling, stomatitis.2 and crusting usually start on the face, bridge of the In the cat, lesions of pemphigus vulgaris nose, and pinnae then gradually spread to the .con1monly affect the gums, !"ips, hard palate, and ventrum. As with the other variants of pemphigus nasal philtrum. 6 Vesicles and bullae are rarely (i.e. -- pemphigus vulgaris), pain and pruritus are seen, thus erosions and ulcers are the usual variable and anorexia, depression, and fever are clinical presentations. The list of differential diag­ seen in severely affected animals.2 noses for ulcerative stomatitis in the cat is quite Scaling and crusting are the most common extensive. According to Manning et al 8 the differ­ clinical signs in cases of pemphigus foliaceus entials include: recurrent necrotizing stomatitis, hence the origin of the name, "foliaceus", mean­ Vincent's stomatitis, renal disease, vitamin defi- ing leafy.10 Noxon and Myers reported a case of

16 Iowa State University Veterinarian 2 pemphigus foliaceus in two Shetland Sheepdog testing. ,6 It is recommended that histopathology littermates. They stated that although "pem­ together with immunopathologic evaluations be phigus foliaceus generally is not regarded as an used as the diagnostic approach to autoimmune autoimmune disease with strong genetic influ­ skin diseases.4,12 Routine blood work (hemogram, ence" they did find two littermates from a litter of serum chenlistries) are usually non-specific in the five that were diagnosed as having pemphigus cases of pemphigus vulgaris and pemphigus foli­ foliaceus. They went on to state that "familial aceus. Results usually reveal a rnild-to-moderate occu rrence of pemphigus foliaceus has been nonregenerative anemia, mild hypoalbuminemia, reported in humans and that development of mild-to-moderate increases in globulins, and with many autoimmune diseases is determined to a pemphigus foliaceus, a slight eosinophilia.2 great extent by inheritance."11 Direct smears should be done on intact ves­ In the cat, pemphigus foliaceus is similar to icles or pustules. The snlears can be stained with what was described above for the dog. It is a variety of preparations including Wright's stain, characterized by facial exfoliative dermatitis around new methylene blue, Quick stain, Sedi stain, and the nose, periorbital area, and the pinnae. 8 As Papanicolau's stain. 12 Microscopic examination with the dog, oral lesions are rare. More com­ will reveal large numbers of neutroprlils and/or monly seen are crusts, scales, alopecia, erosions, eosinophils, few bacteria, and acantholytic ker­ and epidermal collarettes. Footpad lesions can atinocytes. The acantholytic cells are highly also occur. suggestive of pernphigus but do not in themselves Differentials for facial dermatitis in the cat are offer a definitive diagnosis of pemphigus. quite extensive: bacterial folliculitis-furunculosis, Skin biopsies must be done on intact vesicles, fungal dermatitis, demodecosis, allergic dermati­ which may pose a problem in that these vesicles tis (food), solar dermatitis, squamous cell carci­ are very transient and "fragile. Multiple sites may noma (white areas), seborrhea, pemphigus, sys­ need to be biopsied to reveal pathologic changes temic lupus erythematosus, notoedric mange, indicative of pemphigus. Muller et al2 recom­ sarcoptic mange, otodectic mange, and drug erup­ mends hospitalizing the animal in order to check tion. 8 In dogs the differential list is similar: bacte­ its skin every 2 to 4 hours for blisters. They also rial folliculitis, dermatophytosis, demodecosis, go on to state that these "blisters rapidly fill with dermatophilosis, seborrhea, lupus erythemato­ leukocytes and grossly and microscopically ap­ sus, subcorneal pustular dermatosis, sterile eo­ pear as pustules which could confuse both the sinophilic pustulosis, linear IgA dermatosis, zinc­ clinician and the pathologist.2 responsive dermatitis, dermatomyositis, and Histopathologically, "pemphigus vulgaris is Iymphoreticular neoplasia.2 characterized by suprabasilar acantholysis with resultant cleft and vesicle formation." Single epi­ Pemphigus Erythematosus dermal cells remain attached along the underlying basement membrane and resemble "a row of Pemphigus erythematosus, is thought to be a tombstones."2,7 In the cat, classical histopathol­ benign form of pemphigus foliaceus. No age or ogic changes are seldom seen, thus the diagnosis sex predilections are apparent, but Muller et al2 of pemphigus vulgaris may need to be based on states that in dogs, Collies and German Shepards only direct smears and direct immunofluores­ may be predisposed to the disease. Lesions are cence testing. 8 Pemphigus vegetans is charac­ similar to that of pemphigus foliaceus, however, terized histologically by acantholysis, papilloma­ the lesions are restricted to the face and ears. tosis, and intraepidermal microabscesses con­ Depigmentation of the nose is often a complica­ taining acantholytic keratinocytes, eosinophils, tion, thus allowing photodermatitis to be a pos­ and/or neutrophils.2,12 Pemphigus foliaceus and sible sequela.2 Differentials are the same as for pemphigus erythematosus appear histologically pemphigus foliaceus. similar. They are characterized by intragranular or subcorneal cleft and vesicle formation and Diagnosis contain neutrophils or eosinophils along with acantholytic keratinocytes. Cells from the stratum Definitive diagnosis of pemphigus requires a good granulosum are often found attached to the over­ history and physical examination, followed by lying stratum corneum within the vesicle and are direct smears, and histopathologic examination termed granular cell "cling-ons."2 Cats with with immunofluorescence or immunoperoxidase pemphigus foliaceus and pemphigus erythema-

Vol 53, No.1 17 tosus have similar histopathologic changes char­ above recommended dose for initial treatment of acterized by subcorneal blisters and acantholy­ penlphigus has been recognized to control only sis. 8 about 50% of the cases in terms of remission of Muller et al2 also lists histologic findings that clinical signs.2,14 In a study done by Scott et ai, a may aid in the diagnosis of pemphigus in dogs and larger dose of prednisolone was used (6.6 mg/kg/ cats: "(1) a lichenoid cellular infiltrate (mononu­ day) in 31 dogs and proved efficacious in 94% in clear cells, plasma cells, neutrophils, (2) eosino­ terms of inducing a remission of primary skin philic exocytosis and microabscess formation lesions, however, glucocorticoid side effects were within the epidermis or follicular outer root sheath greatly increased.15 Cats seem to respond well to (pemphigus foliaceus, erythematosus, vegetans), glucocorticoid treatment alone and upon resolu­ (3) involvement of the follicular outer root sheath tion of primary lesions, cats, as well as dogs, can in the suprabasilar, intraepidermal, intragranular, be placed on alternate day/night maintenance or subcorneal acantholytic process, and (4) acan­ prednisolone therapy to maintain remission.8 tl1olytic, dyskeratotic granular epidermal cells An alternative method of corticosteroid treat­ ("grains") at the surface of erosions (pemphigus ment in the dog, corticosteroid pulse therapy, foliaceus and erythematosus).2 involves the parenteral administration of meth­ Immunofluorescence or immunoperoxidase ylprednisolone sodium succinate (11 mg/kg IV

toctinrt '::11"'0 noorlorl fAI'" tho rlofiniti\lr'\ r1it""\rtnr'\~i~ ",of Lv,",LII I~ UI v IICiCiUCiU IVI U ICi Uvlll IILI VV ula~llvvlv VI over 1 hour for 3 consecutive days).2.1n This pemphigus after all of the above diagnostic "push­ treatment regime was adapted from human ups" are performed. Direct immunofluorescence medical therapy for autoimmune skin diseases. testing seems to be favored over indirect inl­ According to White et a11 6, corticosteroid pulse munofluorescence due to the high nunlber of therapy proved efficacious in rapidly resolving negative results with the indirect method. It is skin lesions in all the dogs in their study, and did imperative that lesional (intact blisters or pus­ not elicit any of the adverse side effects linked to tules) as well as perilesional skin be biopsied.2,6 high dose corticosteroid therapy. The presence of inlmunoglobulin (usually IgG) Corticosteroids given at immunosuppressive and occasionally complement deposition in the levels have the following effects: "(1) decrease in intercellular substance helps support a definitive circulating lymphocytes and monocytes, (2) de­ diagnosis of pemphigus. crease in certain lymphocyte and monocyte func­ tional capabilities, and (3) decrease in immunog­ Therapy lobulin and complement levels."17 Major side effects in the study done by Scott et al 15 included Therapy of pemphigus is usually based on the polydipsia, polyuria, polyphagia, lethargy, depres­ premise of controlling or managing the clinical sion, muscle wasting, hepatopathy, and pancreati­ manifestations of the disease. This is due to the tis in addition to infection (especially in the urinary fact that medical treatment must be continued for tract), thromboembolism, gastrointestinal hemor­ long periods of time, and often for the life of the rhage, osteoporosis, and cushingoid signs and animal. The goal of therapy is irnrnunosuppres­ symptoms. Gastrointestinal side effects, such as sian to negatively control or regulate immunologic indigestion and ulceration, caused by high doses reactivity. The immunosuppressive agents com­ of corticosteroids can be controlled by including monly used in the clinical management of pem­ cimetidine in the treatment protocol. Although phigus include the corticosteroids alone or in thorough research has not fully documented the conjunction with cytotoxic or imnlunonl0dulating use of cimetidine to control gastrointestinal side agents. effects, its inclusion in the treatnlent protocols has The most widely used glucocorticoid for the been clinically efficacious. initial treatment of pemphigus is prednisolone or Because of the above-mentioned side effects prednisone. Prednisolone must be given in with the use of high doses of corticosteroids, immunosuppressive doses which range trom 2.2 chemotherapy can be used in conjunction with to 4.4 mg/kg orally each day for dogs. Cats need prednisolone. This combination will not only help a higher dose which ranges trom 4.4 to 6.6 mg/kg minimize side effects due to the prednisolone by given orally each day.2,6 The dose can be divided lowering its dose requirements, but will aid in the into two treatments, thus stressing that therapy treatment of pemphigus if corticosteroids alone rnust be individualized in order to minimize ad­ cannot induce remission of the disease. Ihrke et verse side effects (to be discussed below). The al reconlmends instituting combination therapy if

18 Iowa State University Veterinarian the animal has not shown substantial improve­ 3. Jordan RE, Kawana S, Fritz KA. Irnmunopa­ ment within 10 days after corticosteroid therapy thologic mechanisms in pemphigus and bullous was initiated or if the maintenance dosages (less pemphigoid. J Invest Derm. 85: 72-76. 1985. than or equal to 1.1 mg/kg on alternate days) cannot be achieved within 3 to 4 weeks. 1O 4. Medleau L, Oawe OL, Scott OW. Complement Cytotoxic agents and immunomodulating drugs immunofluorescence in sera of dogs with pem­ used include: azathioprine, chlorambucil, cyclo­ phigus foliaceus. Am J Vet Res. 48:486-487. phosphamide, cyclosporine, aurothioglucose, and 1987. dapsone.2,10,14,15 Dapsone has not been approved for use in dogs and cats in the United States and 5. Gornlan NT, Werner LL. Imrnune mediated was not found efficacious in the study done by diseases of the dog and cat. I. Basic Concepts Scott et al. 15 Muller cautions the use of azathi­ and the systemic imrnune-medicated diseases. oprine in cats due to their susceptibility to azathi­ Br Vet J. 142:395-398. 1986. oprine toxicity.2 Although chemotherapy and chrysotherapy 6. Scott OW. Pemphigus in domestic animals. will lower the required dosage of corticosteroids, Clin Derm. 1: 141-152. 1983. these drugs are not without adverse side effects or toxicities. Of the numerous side effects pos­ 7. Scott OW, Manning TO, Smith CA, Lewis RM. sible, depending on the drug chosen, of most Pemphigus vulgaris without mucosal or mucocuta­ importance is myelosuppression which is a com­ neous involvement in two dogs. JAAHA. 401­ mon featu re of all of the above-mentioned cyto­ 404. 1982. toxic or immunomodulating drugs. Thus, monitor­ ing the patient with a hemogram at least once a 8. Manning TO, Scott OW, Smith CA, Lewis RM. month will aid in individualizing a suitable treat­ Pemphigus diseases in the feline: seven case ment regime. Drug dosages should be adjusted reports and discussion. JAAHA. 18:433-443. to maintain a leukocyte count of no lower than 1982. 3000 per rnm 3 to nlinimize risk of infection. Al­ though chrysotherapy has been used success­ 9. Schultz KT, Goldschimdt M. Pemphigus veg­ 10 fully in several studies ,14,15 it is usually not the etans in a dog: a case report. JAAHA. 16: 579­ drug of first choice in the clinical management of 582. 1980. pernphigus. Patients are usually started on corti­ costeroids initially, and possibly combination 10. Ihrke PJ, Stannard AA, Ardans AA, Griffith therapy with azathioprine or cyclophosphamide CEo Pemphigus foliaceus in dogs: A review of 37 later. 2,1o cases. JA VMA. 186: 59-69. 1985. The prognosis for an animal diagnosed as having pemphigus must be guarded due to the 11. Noxon JO, Myers RK. Pemphigus foliaceus possibility of life-long treatment and periodic in two Shetland Sheepdog Iitternlates. JA VMA. monitoring regardless of the treatment regime 194:545-546. 1989. instituted. The study of pemphigus cornplex in dogs and cats has brought many insights into the 12. Akerman LJ. Canine and feline pemphigus diagnosis and treatment of the autoimmune disor­ and penlphigoid. Part I. Pemphigus. Compend der in both animals and humans. Contin Educ Prac Vet. 7:89-97. 1985.

References 13. Suter MM, Palma OG, Zindel S, Schenk H. Pemphigus in the dog: Comparison of immunofluo­ 1. Sams WM Jr., Gammon WR. Mechanism of rescence and immunoperoxidase methods to lesion production in pemphigus and pemphigoid. demonstrate intercellular immunoglobulins in the J Am Acad Derm. 6:431-449. 1982. epidermis. Am J Vet Res. 45:367-369. 1984.

2. Muller GH, Kirk RW, Scott OW. Immunologic 14. Ackerman L. Pemphigus and pemphigoid in diseases. In: Small Animal Dermatology, Phila­ dogs and cats. Part I: Clinical signs, diagnosis delphia: WB Saunders Co. 150-243, 427-574. and treatment. Mod Vet Prac. March:260-265. 1989. 1986.

Vol 53, No.1 19 15. Scott DW, Manning TO, Smith CA, Lewis RM. pulse therapy in five dogs with autoimmune skin Observations on the immunopathology and ther­ disease. JAVMA. 191: 1121-1123. 1987. apy of canine pemphigus and pemphigoid. JAVMA. 180: 48-52. 1982. 17. Fauci AS. Clinical aspects of immunosup­ pression: Use of cytotoxic agents and corticoster­ 16. White SD, Stewart LJ, Bernstein M. Corticos­ oids. In: Immunology III, Bellanti JA, WB Saun­ teroid (methylprednisolone sodium succinate) ders Co. 546-556. 1987.

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