Veterinary Dermatology 2004, 15, 245– 252

Blackwell Publishing, Ltd.

Prolonged remission after immunosuppressive therapy in six dogs with pemphigus foliaceus
THIERRY OLIVRY*, KERSTIN E. BERGVALL†,‡ and BARBARA A. ATLEE§ *Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC 27606, USA †Djur Akuten, Kungstensgatan, S-11329 Stockholm, Sweden ‡Department of Small Animal Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden §Animal Dermatology & Allergy Clinic, 1204 Deboy Street, Raleigh, NC 27606, USA
(Received 23 August 2003; accepted 30 September 2003)

Abstract Limited information is available on the long-term outcome of treatment of pemphigus foliaceus in dogs. The purpose of this study is to report that a prolonged remission can occur after discontinuation of immunosuppressive regimens in some animals with this disease. Six dogs were diagnosed with pemphigus foliaceus based on suggestive clinical signs and histopathology. These patients were treated either with immunosuppressive doses of oral glucocorticoids or with a combination of oral glucocorticoids and azathioprine. After clinical signs underwent complete remission, which occurred 1.5–5 months after immunosuppression was initiated, the drugs were tapered progressively and eventually withdrawn. The total duration of immunosuppressive therapy varied between 3 and 22 months. Skin lesions of pemphigus foliaceus did not recur for 1.5–6 years after treatment was stopped. These observations suggest that, in some dogs with pemphigus foliaceus, immunosuppression can lead to long-term remission of skin lesions, and that discontinuation of treatment is not necessarily followed by a recurrence of clinical signs. Keywords: autoimmunity, blistering dermatoses, canine, desmoglein, desmosome, epidermis, integument, keratinocyte, skin.

Pemphigus foliaceus (PF) represents the most common autoimmune blistering skin disease of dogs.1,2 Its prevalence is estimated to be < 1% of cases presented for skin diseases at university hospitals or examined as surgical biopsy specimens at a university laboratory.1–4 Because the pathogenesis of human and canine PF appears to involve autoantibodies targeting the keratinocyte desmosomal cadherin desmoglein-15–7 standard-ofcare treatment typically consists of immunosuppressive protocols.8,9 Immunosuppression is achieved using either oral glucocorticoids alone or in combination with cytotoxic drugs that include azathioprine, chlorambucil or cyclophosphamide.8,9 Upon remission of clinical signs, the dosage and/or frequency of administration of either glucocorticoids or cytotoxic drugs, or both, are reduced gradually to decrease the risk of adverse drug events.2,3 Information on long-term treatment outcome and prognosis of large cohorts of dogs with PF has not been published at this time. In the largest published case series of dogs with PF, with follow-up of 1–7 years, immunosuppressive therapy was deemed successful in
Correspondence: T. Olivry, DrVet, PhD, Department of Clinical Sciences, North Carolina State University, College of Veterinary Medicine, 4700 Hillsborough Street, Raleigh, NC 27606, USA. E-mail: © 2004 European Society of Veterinary Dermatology

only 18 of 34 subjects (53%).3 Furthermore, other reports provide evidence for a wide variation in prognosis among patients. At one end of the disease spectrum, some dogs with PF are killed because of a lack of response of lesions to immunosuppression.2,10 In contrast, a single dog with PF was reported to have remained free of lesions for at least 1 year after discontinuation of prednisolone administration (case 2 in Bensignor & Carlotti11). The purpose of this study was to describe the clinical course of PF lesions in six dogs in which discontinuation of immunosuppressive therapy led to long-term remission with no recurrence of disease for at least 1.5 years after the cessation of treatment.

C A SE R E P O RT S Selection
Medical records from three dermatology referral clinics were searched for affected dogs that satisfied the following criteria during the period 1995–2001: 1 clinical signs suggestive of PF (pustules, erosions and crusts with bilaterally symmetrical distribution affecting primarily the face). 2 histopathological examination of lesional skin biopsies diagnostic for PF (intraepidermal pustules rich in acantholytic keratinocytes).


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3 positive clinical response to immunosuppressive protocols that included glucocorticoids with or without cytotoxic drugs. 4 lack of recurrence of clinical signs of PF for at least 1 year after discontinuation of immunosuppressive medications. At the North Carolina State University College of Veterinary Medicine (Raleigh, NC, USA), 27 dogs were diagnosed with PF based on criteria 1 and 2 during the study period. Two of these subjects (7%) fulfilled additional criteria 3 and 4. At the Animal Dermatology and Allergy Clinic (Cary/ Durham, NC, USA), 15 dogs were diagnosed with PF. Two dogs (13%) fulfilled all four criteria necessary for inclusion in this report. At the Djur Akuten specialty clinic (Stockholm, Sweden), nine dogs were diagnosed with PF per criteria 1 and 2. Two dogs (22%) also satisfied inclusion criteria 3 and 4. In all, six dogs with PF in long-term remission without treatment are reported herein.

Figure 2. Skin; case 1: a subcorneal pustule contains neutrophils and acantholytic keratinocytes. Haematoxylin and eosin, bar = 75 µm, inset = 50 µm.

Case 1
A 1.5 year-old female spayed Doberman pincher dog was presented with a 2-month history of generalized pustular eruption, scaling and crusting that initially affected the face, limbs and abdomen. Drugs had not been administered prior to the appearance of the first skin lesions. Superficial pyoderma was diagnosed by the general practitioner based on a culture of Staphylococcus intermedius (location of sampling unknown). Owing to a lack of improvement after successive prescriptions of cephalexin, amoxicillin–clavulanate, oxacillin, prednisone and griseofulvin, the dog was referred to a dermatologist. On clinical presentation, the dog was febrile (40.5 °C). Large irregular pustules were found on the ventral abdomen, axillae and near auditory orifices. Scattered eroded and crusted lesions were present at various locations on the body, especially on the dorsal and lateral muzzle and around the eyes, where the lesions exhibited a bilateral symmetry (Fig. 1a,b). Aspiration cytology of pustule content revealed intact neutrophils and numerous acantholytic keratinocytes. Histopathological examination of skin biopsy specimens exposed subcorneal neutrophilic pustules with

isolated and clustered acantholytic keratinocytes (Fig. 2). periodic acid Schiff (PAS) staining of skin sections was unremarkable. A fungal culture of crusts and hair was negative. Direct immunofluorescence (IF) testing, performed as described previously,12 confirmed the presence of intercellular immunoglobulin (Ig)G and IgA deposited in the upper half of the epidermis. Indirect IF testing was negative on canine lip and tongue substrates.12 A diagnosis of PF was made based on clinical signs, histopathology results and direct IF testing. Treatment was initiated with prednisone at 60 mg (2.0 mg/kg) twice daily. After 3 weeks, new pustules erupted, and erosions and crusts appeared on the footpads. Azathioprine was added at 50 mg (1.5 mg/ kg) once daily, and the dose of prednisone was decreased to 40 mg (1.3 mg/kg) twice daily to reduce side effects of glucocorticoid therapy. Because of a lack of perceived efficacy after 2 weeks, the dose of azathioprine was doubled to 100 mg (3.3 mg/kg) once daily. Complete remission of skin lesions occurred within 2 months, and the dose of prednisone was tapered to 40 mg once daily. During the following 5 months, the dose of prednisone was decreased by 25% every 2 weeks, on an alternate-day basis, and the lesions remained in complete

Figure 1. Case 1: bilaterally symmetrical erosions and crusts can be seen around the eyes (a) and on the dorsal (a) and lateral muzzle (b). © 2004 European Society of Veterinary Dermatology, Veterinary Dermatology, 15, 245– 252

Remission of canine pemphigus foliaceus remission. During the ensuing 2 months, azathioprine was administered on an every other day basis at the same dose. All medications were discontinued eventually after 10 months of immunosuppression. Skin lesions of PF did not recur during the subsequent 6 years.


Case 2
A 4 year-old female intact German shepherd crossbred dog was presented with a 1-month history of pruritic facial lesions. Medications had not been given before cutaneous signs were observed. One week prior to presentation to the dermatologist, lethargy, depression and fever (40 °C), arose, and skin lesions spread to the limbs. The dog walked reluctantly. Dermatological examination revealed large flaccid pustules with a peripheral erythematous halo on the abdomen. Erosions and crusts were generalized, and they were present in highest numbers on the face, ears, genitalia and tail. The periphery of most footpads was crusted and fissured. Fine-needle aspiration of the content of abdominal pustules revealed numerous intact neutrophils and isolated or clustered acantholytic keratinocytes. Histopathological examination of pustular skin lesions uncovered the presence of large subcorneal pustules with numerous acantholytic keratinocytes. Staining with PAS did not reveal corneophilic dermatophytes. A dermatophyte culture of scales and crusts was unremarkable after 2 weeks. Indirect IF on mouse skin was negative at 1:50 dilution. The diagnosis of PF was based on clinical and histopathological findings. Prednisone was prescribed at 40 mg (2.0 mg/kg) twice daily. Two weeks later, a marked improvement in the severity of skin lesions was seen, and the dose of prednisone was decreased to 30 mg (1.5 mg/kg) twice daily for 2 weeks, then to 20 mg (1.0 mg/ kg) twice daily for another 2 weeks. At that time, complete clinical remission was achieved and prednisone was administered at 20 mg once daily for 1 month. Because of persistent remission, prednisone was given on alternate days with decreasing dosages, and it was discontinued after 6 months. Almost 2 years after cessation of glucocorticoid therapy, the disease remains in complete remission.

Figure 3. Case 3: depigmentation, erythema, scales and crusts are visible on the dorsal muzzle (a), while the dorsal and frontal aspects of the nasal planum are depigmented, erythematous, eroded and crusted (b).

Figure 4. Skin; case 3: IgG is deposited around keratinocytes of perilesional skin. The intensity of staining is strongest in the stratum spinosum. Direct IF, anticanine IgG-fluorescein (green colour), Evans’ blue and propidium iodide (red nuclear colour) counterstains, bar = 25 µm.

Case 3
A 4 year-old Australian shepherd dog had a 1-year history of depigmentation, erosions and crusting of the nasal planum and dorsal muzzle. The patient was receiving no medications when skin lesions were noticed first. Prednisone (uncertain dosage) was administered for suspected discoid lupus erythematosus, and this treatment resulted in temporary remission of skin lesions. Because of adverse effects of glucocorticoids, therapy was switched to a niacinamide–tetracycline combination, topical hydrocortisone cream, sun avoidance and a diet change. When skin lesions worsened, the dog was referred. Upon presentation to the dermatologist, the nasal planum had lost its normal cobblestone surface architecture; it was depigmented, erythematous, eroded and crusted (Fig. 3 and inset). Scales and crusts

covered the dorsal muzzle (Fig. 3). Several large erythematous, oedematous and crusted plaques were present on the lateral trunk. A Wood’s lamp examination was unremarkable. A dermatophyte culture of hair and crusts did not yield any growth. Antinuclear antibodies were not detected at 1:40 dilution. Microscopic examination of skin biopsies revealed subcorneal pustules rich in neutrophils and acantholytic keratinocytes. Direct IF confirmed the presence of IgG surrounding epidermal keratinocytes, especially those of the stratum spinosum (Fig. 4). Indirect IF, performed on neonatal mouse skin, revealed antikeratinocyte IgG auto-antibodies at up to 1:250 dilution. The diagnosis of PF was made based on clinical signs, as well as results of histopathology and IF assays. Pending reception of test results, oral cephalexin, a topical glucocorticoid solution and fatty acid supplements were prescribed. Because skin lesions did not respond to this regimen, immunosuppression was initiated with prednisone at 20 mg (0.8 mg/kg) twice daily and azathioprine 50 mg (1.9 mg/kg) once daily.

© 2004 European Society of Veterinary Dermatology, Veterinary Dermatology, 15, 245–252


T Olivry et al. obtained. Clindamycin was given at 300 mg (5.5 mg/ kg) twice daily for 3 weeks. Baths with ethyl lactate (Etiderm, Virbac, Fort Worth, TX, USA) were recommended. Ear flushes and a topical antibiotic–antifungal–glucocorticoid formulation were prescribed (Otomax, ScheringPlough Animal Health, Union, NJ, USA) for treatment of the otitis externa. Flea control was implemented. After 3 weeks of antibiotic and glucocorticoid administration, most lesions had begun to heal, but new pustules continued to erupt. Remaining crusts were large, thick and often confluent. Large pustules, evolving from an erythematous base, were present over the sternum and axillae. The footpads remained hyperkeratotic. Cytological examination of the pustules revealed neutrophils, cocci and acantholytic keratinocytes. Because clinical signs were deemed most consistent with the diagnosis of PF, azathioprine was added at 75 mg (1.4 mg/kg) once daily and the dose of prednisone was decreased to 40 mg (0.7 mg/kg) once daily to reduce the occurrence of adverse side effects. Also, oral clindamycin and ethyl lactate shampoos were to be continued for an additional 10 days. Two weeks later, all pustules had healed, and new lesions had not developed. The footpads were affected less severely than before. The dose of prednisone was decreased to 30 mg (0.6 mg/kg) once daily, whereas azathioprine was continued at the same dose. After 2 weeks, the owner reported that remission was complete. The owner had independently reduced the dose of prednisone to 20 mg (0.4 mg/kg) in the last week, but skin lesions had not recurred. During the ensuing months, the dose of both drugs was reduced progressively by the referring veterinarian, and treatment was discontinued eventually after 6 months of immunosuppression. Skin lesions did not recur during the subsequent 2 years.

Three weeks later, the lesions had markedly decreased in severity, and the dose of prednisone was reduced to 30 mg (1.1 mg/kg) one day and 20 mg the next, whereas that of azathioprine remained at 50 mg once daily. One month later, the skin lesions were almost in complete remission. During the following 17 months, as all skin lesions had regressed completely, the dosage of both drugs was reduced progressively. All medications were discontinued eventually 22 months after immunosuppression was initiated. Three and a half years later, the disease has remained in complete remission without any treatment.

Case 4
A 2.5 year-old female intact Irish wolfhound was presented to the referring veterinarian with a 1-month history of multifocal erythematous and crusted papules on the trunk, erythematous pododermatitis and lameness. Medications had not been administered before the owner noticed skin lesions. Cephalexin was prescribed for 14 days, and upon observation of footpad exfoliation, this antibiotic was changed to trimethoprim–sulfamethoxazole, then to enrofloxacin. Despite therapy, lesions continued to worsen, and pruritus became more severe. Upon referral to the dermatologist, the dog was depressed. The pinnae were oedematous, erythematous, excoriated and painful. The ear canals were eroded and filled with purulent fluid. Large dried erythematous pustules and crusts, often overlying an erythematous base, were present over the entire body, including the head and muzzle. The footpads were hyperkeratotic and fissured. Erythema and erosions were noticed in intertriginous areas of the abdomen, inguinal region and perineum. Lesions were not observed on mucosal surfaces. Impression smears of pus collected under dried crusts revealed few cocci and neutrophils, but no obvious acantholytic keratinocytes. Ear cytology was consistent with suppurative bacterial and yeast otitis externa. Skin biopsies were collected from four crusted pustules and microscopic examination of sections revealed epidermal hyperplasia, hyperkeratosis and subcorneal neutrophilic pustules with acantholytic keratinocytes. Scattered bacterial colonies were seen on the skin surface. Neutrophils, lymphocytes, plasma cells and macrophages surrounded superficial dermal blood vessels. Additional staining with PAS did not reveal any dermatophytes. Examination with a Wood’s lamp and a dermatophyte culture of hair and scales were unremarkable. Indirect IF, performed on neonatal mouse skin, uncovered the presence of circulating antikeratinocyte IgG auto-antibodies (1:500 titre). Pemphigus foliaceus, secondary pyoderma and mixed suppurative mixed bacterial and yeast otitis externa were diagnosed from clinical signs and results of cytological, histological and IF tests. Pemphigus skin lesions were treated with prednisone at 40 mg (0.7 mg/kg) twice daily to be reduced to once daily administration after clinical remission was

Case 5
A 5-year-old female intact akita inu dog was presented to the dermatologist with a 4-month history of facial crusting and alopecia. The dog had not been given any drugs in the period immediately preceding the onset of skin lesions. A 1-month course of cephalexin was not followed by any noticeable decrease or worsening in extent or severity of cutaneous signs. On clinical examination by the dermatologist, the dog was alert, normothermic and appeared in good general health. Easily removed crusts were found on the concave aspect of the pinnae, dorsal muzzle, nasal planum and around the eyes. Skin lesions exhibited a bilateral symmetry. A few intact pustules were observed on the concave aspect of both pinnae. Fine-needle aspiration of intact pustules, as well as imprints of the underside of exfoliated crusts, revealed intact neutrophils and either isolated or clustered acantholytic keratinocytes. Fungal culture of hairs and crusts was unremarkable. Histopathological examination of skin biopsy specimens revealed subcorneal pustular dermatitis with acantholytic keratinocytes. A

© 2004 European Society of Veterinary Dermatology, Veterinary Dermatology, 15, 245– 252

Remission of canine pemphigus foliaceus diagnosis of PF was made based on clinical signs, results of histopathology and exclusion of corneophilic dermatophyte infestation. Treatment was initiated with prednisolone at the dose of 35 mg (1.0 mg/kg) twice daily and topical application of 0.1% betamethasone valerate cream (Celeston Valerat, Schering-Plough AB, Stockholm, Sweden). After 3 weeks, owing to unacceptable adverse effects, the dosage of prednisolone was reduced to 17.5 mg (0.5 mg/kg) twice daily, and azathioprine was added at 50 mg (1.4 mg/kg) every other day. One week later, the severity of skin lesions had improved markedly, but lesions still persisted on the nose and around the eyes. Prednisolone was no longer administered on the days when the patient received azathioprine. Betamethasone valerate cream was still used topically as needed to control the remaining skin lesions. After an additional 3 weeks, the disease was considered to be in complete remission. Topical therapy was discontinued, and prednisolone was tapered to 35 mg (1.0 mg/kg) every other day; azathioprine was continued at 50 mg (1.4 mg/kg) every other day. Two weeks later, the disease remained in remission and hair began to regrow. The dosage of prednisolone was decreased to 15 mg (0.4 mg/kg) every other day. Azathioprine was continued as before. Ten days later, after 3 months of immunosuppression, the owner discontinued all medications without instructions, and skin lesions of PF did not recur during the following 18 months.


Figure 5. Case 6: depigmentation, erythema, erosions, scales and crusts are distributed bilaterally and symmetrically on the dorsal muzzle, around the eyes and on the pinnae.

Case 6
A 7.5-year-old intact male Eurasier dog, a breed related to the chow-chow, was presented to the dermatologist with a 6-month history of dermatitis. There was no history of drug administration prior to the development of skin lesions. Preputial erythema and facial crusting were the first skin lesions observed. Treatment with cephalexin and prednisolone (dosages unknown) for 2 weeks led to partial improvement, but clinical signs worsened after discontinuation of the drugs. On physical examination, the dog appeared in good general health. Mild hyperthermia was attributed to excitement. Alopecia and nonadherent crusts were seen, in a bilateral and symmetrical pattern, around the eyes, dorsal muzzle (Fig. 5), ear pinnae, prepuce and scrotum. The footpads were dry, fissured and crusted. Crusts were also seen around the base of few claws. Cytological examination of impression smears revealed neutrophils and acantholytic keratinocytes. A dermatophyte culture, performed on both hair shafts and crusts, was negative. Histopathological examination of lesional skin biopsies uncovered a neutrophilic subcorneal pustular dermatitis with acantholytic keratinocytes. A diagnosis of PF was made from clinical, histological and cytological findings Immunosuppression was initiated with prednisolone at 30 mg (1.2 mg/kg) twice daily. Five days later, the owner reported unacceptable adverse effects from this treatment, so the dose of prednisolone was reduced to 50 mg (2.0 mg/kg) every other day. Azathioprine was

given at 50 mg (2.0 mg/kg) on the days without prednisolone. After 3 weeks of this regimen, few crusts remained, but the footpads were still fissured. Prednisolone was given at 25 mg (1.0 mg/kg) every other day, whereas the prescription of azathioprine was unchanged. Three weeks later, the owner elected to discontinue glucocorticoid administration because of persisting polyuria and polydipsia. At that time, however, the disease was considered to be in complete remission. After 2 weeks, the dose of azathioprine was reduced to 25 mg (1.0 mg/kg) every other day, and the hair began to regrow in previously alopecic areas. Five weeks later, 3.5 months after initiation of immunosuppression, the administration of azathioprine was discontinued. Except for persistent mild alopecia on the dorsal muzzle, as well as dry footpads, the disease has been considered to be in remission without treatment for the last 18 months.

Here, we report the evolution of PF in six dogs for which immunosuppression led to complete remission of skin lesions, and discontinuation of treatment was not followed by a recrudescence of the disease for follow-up periods varying from 1.5 to 6 years. In total, 51 dogs seen at three dermatology clinics met the study criteria for a diagnosis of PF, and 6 of the 51 (12%) experienced a long-term remission after discontinuation of immunosuppressive drugs. To the authors’ knowledge, such a remarkable long-term treatment outcome had been reported only once before (case 2 in Bensignor & Carlotti11).

© 2004 European Society of Veterinary Dermatology, Veterinary Dermatology, 15, 245–252


T Olivry et al. azathioprine for 7.5 months, one (case 2) was given high dosages of prednisolone for 8.5 months, the last patient received only low dosages of prednisone for 7 months, and case 3 was not treated with antiinflammatory medications.18 In that study, therefore, two of four patients had needed months of immunosuppression before all treatment was discontinued. Although one cannot discount the authors’ hypothesis that their patients were affected with drug-associated pemphigus, one cannot disprove the contra-hypothesis either. Indeed, it is conceivable that these animals could have suffered from natural autoimmune PF similarly to the six dogs reported here. If this alternative hypothesis were to be considered, then the administration and subsequent withdrawal of ‘culprit’ drug(s) would have had no influence on disease evolution in at least two of four dogs diagnosed with ‘drug-related PF’. Unfortunately, the question of which hypothesis to accept will remain unanswered as drug re-challenges were not performed in any of these dogs for valid ethical reasons. Nevertheless, our observations suggest that the lack of recurrence of pemphigus lesions after discontinuation of immunosuppression cannot be used as a criterion for diagnosing drug-related PF in dogs. A retrospective cohort study recently investigated the long-term outcome of treatment in human beings with PV.19 Among other valuable follow-up information, the authors reported rates of complete remission, defined by ‘a period of more than one month during which the patient was receiving no systemic therapy and was lesion free’. Complete and long-lasting remissions were induced in 25, 50 and 75% of 40 patients 2, 5 and 10 years after diagnosis, respectively. Two factors were identified to predict the course of PV in these subjects. The first parameters were the initial severity and extent of the disease, with patients affected with mild to moderate PV being twice as likely to enter complete remission than those with severe phenotype. The other factor was a rapid response to immunosuppression. Patients whose lesions responded early to therapy were more than twice as likely to enter prolonged remission than those with delayed response to treatment. The six dogs described in this report exhibited variable phenotypes of PF, with lesional extent ranging from localized to the face (case 5) to generalized (cases 1, 3 and 4), and severity varying from mild (case 5) to severe (case 4). Such observations suggest that extent and severity of skin lesions are unlikely to be useful factors for predicting long-term remission in dogs with PF. In contrast, and similarly to observations reported by Herbst & Bystryn in human beings with PV19 a rapid response of skin lesions to immunosuppression might be a factor helpful for predicting long-term treatment evolution of canine PF. Indeed, complete remission of skin lesions occurred shortly after immunosuppression was initiated in the six patients described herein (median: 2 months; range: 1.5–4.7 months). Such short durations could empirically qualify as

In the six dogs described here, the diagnosis of PF was made from collation of clinical signs along with typical histopathological findings.3,9 Moreover, in three of four patients (75%), immunological tests revealed the presence of skin-fixed or circulating antikeratinocyte IgG auto-antibodies, supporting the diagnosis of PF. Also, pustular dermatophytosis, a PF-like eruption caused by corneophilic dermatophytosis13,14 was ruled out in all patients based on results from histopathology and dermatophyte cultures. In only one patient (dog no. 4), was the existence of concurrent bacterial impetigo, a known PF-mimicker, considered possible. In this dog, bacteria were seen on microscopic examination of cytology specimens and at the surface of sections of skin biopsies. However, lesions failed to respond to the administration of three different antibiotics, and they did not recur after antibiotics were discontinued, a noticeable finding in light of continuing glucocorticoid administration. To determine with certainty whether or not a disease is caused by pre-existing drug administration is almost impossible short of re-challenging the subjects with the suspected medication(s). However, such drug provocation is rarely performed for ethical reasons and to decrease harm to patients. Therefore, for most human and animal individuals, the diagnosis of drug-induced skin disease usually remains speculative. Because four of six of the patients reported herein had been treated at some points with cephalexin for the suspected initial diagnosis of pyoderma, one could hypothesize that these dogs were affected with cephalexin-induced or -triggered PF. Indeed, cephalosporins exhibit the potential to induce pemphigus lesions, not due to the presence of thiol (sulfhydryl) radicals, but because they possess an active amide group.15 As an anecdotal proof of such capability, cefadroxil has been reported to induce pemphigus vulgaris (PV) in a human patient.16 We do not consider as valid the hypothesis that PF was induced or triggered by cephalexin in our patients for the following reasons: (i) four of our five dogs were affected with facial lesions prior to the prescription of cephalexin, and facial lesions are seen more commonly during PF than superficial pyoderma; (ii) in four dogs that received cephalexin (cases 1, 3, 5 and 6), cephalexin administration did not result in a worsening of skin lesions, as would be expected in cephalexin-induced PF; (iii) in human individuals, beta-lactamin antibiotic administration triggers the deeper form of pemphigus (PV) instead of the superficial variant reported here.17 Finally, (iv) the incubation period for nonthiol drugtriggered human PV is reported to be greater than 4 months, a duration not compatible with the histories recorded for our patients.17 Recently, PF suspected to be associated to previous drug administration was reported in four dogs.18 In these subjects, the diagnosis of drug-related PF was based on history, clinical signs, histopathology and response to withdrawal of suspected causative drug(s). In this study, however, one subject (case 1) was treated with immunosuppressive doses of prednisolone and

© 2004 European Society of Veterinary Dermatology, Veterinary Dermatology, 15, 245– 252

Remission of canine pemphigus foliaceus ‘rapid’ remissions. Nonetheless, a cohort study is needed to validate whether ‘time to complete remission’ is a parameter useful for predicting the evolution of PF in dogs. In conclusion, our observations suggest that, in some dogs with PF, immunosuppression can lead to rapid remission of skin lesions, and signs will not recur for at least 1.5 years after discontinuation of treatment. This anecdotal report supports the recommendation for dose reduction and eventual discontinuation of immunosuppressive drugs after achieving complete remission of PF skin lesions. Such practice should result in maximal benefit from immunosuppressive regimens while minimizing harm associated with prolonged use of these drugs.


1. Werner LL, Brown KA, Halliwell REW. Diagnosis of autoimmune skin disease in the dog: correlation between histopathologic, direct immunofluorescent and clinical findings. Veterinary Immunology and Immunopathology 1983; 5: 47 – 64. 2. Scott DW, Walton DK, Slater MR et al. Immunemediated dermatoses in domestic animals: ten years after – Part I. Compendium on Continuing Education for the Practicing Veterinarian 1987; 9: 424 – 35. 3. Ihrke PJ, Stannard AA, Ardans AA et al. Pemphigus foliaceus in dogs: a review of 37 cases. Journal of the American Veterinary Medical Association 1985; 186: 59 – 66. 4. Kuhl KA, Shofer FS, Goldschmidt MH. Comparative histopathology of pemphigus foliaceus and superficial folliculitis in the dog. Veterinary Pathology 1994; 31: 19– 27. 5. Iwasaki T, Shimizu M, Obata H et al. Detection of canine pemphigus foliaceus autoantigen by immunoblotting. Veterinary Immunology and Immunopathology 1997; 59: 1 – 10. 6. Diaz LA, Giudice GJ. End of the century overview of skin blisters. Archives of Dermatology 2000; 136: 106– 12.

7. Anhalt GJ, Diaz LA. Research advances in pemphigus. Journal of the American Medical Association 2001; 285: 652–4. 8. Tóth G, Jonkman MF. Therapy of pemphigus. Clinics in Dermatology 2001; 19: 761–7. 9. Olivry T, Chan LS. Autoimmune blistering dermatoses in domestic animals. Clinics in Dermatology 2001; 19: 750– 60. 10. McEwan NA, McNeil PE, Kirkham D. Pemphigus foliaceus: a report of two cases in the dog. Journal of Small Animal Practice 1986; 27: 567–75. 11. Bensignor E, Carlotti D-N. A propos de quatre cas de pemphigus foliacé avec atteinte exclusive des coussinets. Pratique Médicale et Chirurgicale de l’Animal de Compagnie 1997; 32: 481–90. 12. Olivry T, Fine J-D, Dunston SM et al. Canine epidermolysis bullosa acquisita: circulating autoantibodies target the aminoterminal noncollagenous (NC1) domain of collagen VII in anchoring fibrils. Veterinary Dermatology 1998; 9: 19–31. 13. Parker WM, Yager JA. Trichophyton dermatophytosis – a disease easily confused with pemphigus erythematosus. Canadian Veterinary Journal – Revue Veterinaire Canadienne 1997; 38: 502–5. 14. Poisson L, Mueller RS, Olivry T. Dermatophytose pustuleuse cornéophilique canine évoquant un pemphigus foliacé [Canine pustular dermatophytosis of the stratum corneum mimicking pemphigus foliaceus]. Pratique Medicale et Chirurgicale de L Animal de Compagnie 1998; 33: 229–34. 15. Wolf R, Brenner S. An active amide group in the molecule of drugs that induce pemphigus: a casual or causal relationship? Dermatology 1994; 189: 1–4. 16. Wilson J, Koren JF, Daniel RC, Chapman SW. Cefadroxilinduced ampicillin-exacerbated pemphigus vulgaris: case report and review of the literature. Drug Intelligence and Clinical Pharmacy 1986; 20: 219–23. 17. Wolf R, Tamir A, Brenner S. Drug-induced versus drugtriggered pemphigus. Dermatologica 1991; 182: 207–10. 18. White SD, Carlotti DN, Pin D et al. Putative drugrelated pemphigus foliaceus in four dogs. Veterinary Dermatology 2002; 13: 195–202. 19. Herbst A, Bystryn JC. Patterns of remission in pemphigus vulgaris. Journal of the American Academy of Dermatology 2000; 42: 422–7.

Résumé Peu de données sont disponibles sur le pronostic au long cours du pemphigus foliacé (PF) chez le chien. Le but de cet article est de rapporter qu’une rémission prolongée peut survenir chez certains animaux souffrant de cette maladie après arrêt des traitements immunosuppresseurs. Six chiens présentant un PF (diagnostic clinique et histopathologique) ont été traités avec soit des doses immunosuppressives de glucocorticoïdes oraux soit avec l’association de corticoïdes et d’azathioprine. Après disparition des signes cliniques, soit 1.5 à 5 mois après la mise en place du traitement, les doses ont été progressivement diminuées et éventuellement stoppées. La durée totale du traitement immunosuppresseur a varié entre 3 et 22 mois. Les lésions de PF n’ont pas rechuté 1.5 à 6 ans après cessation de la thérapeutique. Ces observations suggèrent que dans certains cas de PF, l’immunosuppression peut permettre une rémission prolongée des lésions cutanées, et que l’arrêt de la thérapeutique n’est pas nécessairement suivi par une rechute. Resumen La información existente sobre el resultado a largo plazo del tratamiento del pénfigo foliáceo (PF) en perros es escasa. El propósito de este artículo es mostrar que se puede producir una remisión prolongada después de retirar la terapia inmunosupresora en algunos animales con esta enfermedad. Se habían diagnosticado seis perros con PF, basado en síntomas clínicos indicativos y en la histopatología. Estos pacientes fueron tratados con dosis inmunosupresoras de glucocorticoides orales, o con una combinación de glucocorticoides orales y azatioprina. Después de la completa remisión de los síntomas clínicos, lo que se produjo entre 1.5 y 5
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meses después de iniciarse la inmunosupresión, la medicación fue reducida progresivamente y eventualmente retirada. La duración total de la terapia inmunosupresora varió entre 3 y 22 meses. Las lesiones cutáneas de PF no recidivaron en 1.5 a 6 años después de finalizar el tratamiento. Estas observaciones sugieren que, en algunos perros con PF, la inmunosupresión puede llevar a una remisión de las lesiones cutáneas a largo plazo, y la retirada del tratamiento no necesariamente es seguida por una recidiva de los signos clínicos. Zusammenfassung Über die Langzeitergebnisse der Behandlung von Pemphigus foliaceus (PF) bei Hunden sind nur begrenzt Informationen verfügbar. Zweck dieses Artikels ist es, darüber zu berichten, dass bei einigen Tieren mit dieser Erkrankung eine anhaltende Remission nach Beendigung von immunsuppressiven Behandlungen auftreten kann. Bei sechs Hunden wurde PF aufgrund von entsprechenden klinischen Anzeichen und Histopathologie diagnostiziert. Diese Patienten wurden entweder mit immunsuppressiven Dosen oraler Glukokortikoide oder mit einer Kombination von oralen Glukokorticoiden und Azathioprine behandelt. Nachdem die klinischen Anzeichen in vollständige Remission gegangen waren, was zwischen 1,5 und 5 Monaten nach Einleitung der Immunsuppression eintrat, wurden die Medikamente nach und nach reduziert und schließlich abgesetzt. Die Gesamtdauer immunsuppressiver Therapie variierte zwischen 3 und 22 Monaten. Hautläsionen durch PF kehrten für 1,5 bis 6 Jahre nach Absetzen der Therapie nicht wieder. Diese Beobachtungen lassen vermuten, daß bei einigen Hunden mit PF die Immunsuppression zu einer Langzeitremission der Hautläsionen führen kann und daß eine Beendigung der Behandlung nicht notwendigerweise ein Wiederauftreten der klinischen Anzeichen nach sich zieht.

© 2004 European Society of Veterinary Dermatology, Veterinary Dermatology, 15, 245– 252