ReviewBlackwell Publishing LtdA review of autoimmune skin diseases in domesticanimals: I – Superficial pemphigusThierry Oli...
Olivry   From data published in one article, the incidence of            studies found that PF could affect both very youn...
Superficial pemphigus in domestic animalsmentioned above could have suffered from natural auto-immune PF that went into pro...
OlivryFigure 4. Canine PF. This 3-year-old English bulldog was affectedwith lesions that progressed rapidly from the face ...
Superficial pemphigus in domestic animalsFigure 8. Feline PF. Alopecia, erosions and crusts developed on theface of a 1.5-y...
OlivryFigure 13. Canine (left) and feline (right) PF. In these early microscopic lesions, fluid-filled vesico-pustules conta...
Superficial pemphigus in domestic animalsFigure 16. Feline PF. Large subcorneal neutrophilic acantholytic pustule   Figure ...
Olivry                                                                      Figure 19. Canine PF. Only rare sera from dogs...
Superficial pemphigus in domestic animals                                                                           More re...
OlivryRecent pharmacological data, however, have shown that              human cicatricial pemphigoid within the spectrum ...
Superficial pemphigus in domestic animalsFigure 21. canine ‘PE’. A 2-year-old colliepresented with a pustular, erosive andc...
Olivrypemphigus’ to regroup cases previously diagnosed as               years of continuous technical support by Stan Duns...
Superficial pemphigus in domestic animals22. Iwasaki T, Yamakita-Yoshida K. Time course of autoantibodies and             a...
Olivry      of binding site of serum antibodies in pemphigus foliaceus                    criteria, pathogenic factors, me...
Superficial pemphigus in domestic animalshistopatología, inmunopatología y resultados del tratamiento de las variantes de p...
Penfigo artigo
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  1. 1. ReviewBlackwell Publishing LtdA review of autoimmune skin diseases in domesticanimals: I – Superficial pemphigusThierry Olivry acquisita (collagen VII).1 Similarly, autoantibodies targeting desmosomal proteins in keratinocytes may result inCenter for Comparative Medicine and Translational Research and blistering diseases of the pemphigus group. This groupDepartment of Clinical Sciences, College of Veterinary Medicine, encompasses both deep (pemphigus vulgaris: desmoglein-North Carolina State University, Raleigh, North Carolina, USA 3 ± desmoglein-1; paraneoplastic pemphigus: desmoglein-Correspondence: Thierry Olivry, Department of Clinical Sciences,North Carolina State University, College of Veterinary Medicine, 3, plakins) and superficial variants (pemphigus foliaceus:Research Building, 4700 Hillsborough Street, Raleigh, NC 27606, desmoglein-1; IgA pemphigus, desmocollin-1 and 3).1USA. E-mail: In animals, autoimmune blistering skin diseases were first recognized 30 years ago, with the seminal description of pemphigus vulgaris in dogs.2,3 Since then, most animalAbstract homologues of the human entities have been identified. ItIn humans, the pemphigus denomination encompasses is the aim of the forthcoming series of reviews to compilea group of autoimmune blistering skin diseases with the latest knowledge on autoimmune skin diseases knownintraepidermal separation resulting from cell–cell in domestic animal species. The first monograph of thisdetachment by acantholysis. Entities are classified series covers information on the epidemiology, clinicalbased on the level of blistering in the epidermis, and signs, treatment outcome, pathology and immunology ofboth superficial (pemphigus foliaceus, IgA pemphigus) superficial variants of pemphigus in dogs, cats, horses andand deep (pemphigus vulgaris, pemphigus vegetans goats. Diseases highlighted herein are pemphigus foliaceusand paraneoplastic pemphigus) variants are recognized. (PF), pemphigus erythematosus (PE) and the so-calledIn domestic animals, subsets of pemphigus have been ‘panepidermal pustular pemphigus’ (PPP).recognized since the mid-1970s, and the disease classi-fication resembles that used for human patients. Thisarticle reviews up-to-date knowledge on the epide- Pemphigus foliaceusmiology, clinical signs, histopathology, immunopathology Historyand treatment outcome of superficial pemphigus in The first article describing the existence of PF in dogs wasdomestic animals. Detailed information on canine, published in 1977 by Halliwell and Goldschmidt.4 Sincefeline, equine and caprine pemphigus foliaceus, canine then, this canine disease has been reported worldwide inand feline pemphigus erythematosus and canine countless articles, each reporting one or few cases. Onlypanepidermal pustular pemphigus is provided. three retrospective studies of large series of subjects (37, 26 and 91 cases) have been published in English.5 –7 TheAccepted 01 August 2006 first report of feline PF was in 1982,8 and there are only two papers describing more than 10 cases each.6,9 Pem- phigus foliaceus was recognized in horses in 1981,10 and three articles report multiple patients.6,11,12 Finally, PF is a rare autoimmune disease of goats and only scattered reports exist.13–16IntroductionEpidermal cells possess structures that are involved Incidence and prevalenceeither in cell–cell (desmosomes) or in cell–matrix adhesion Very little epidemiological information on canine PF is(hemidesmosomes-anchoring fibrils complex). Whenever available, unfortunately. In a veterinary teaching hospitalautoantibodies target proteins in these adhesion struc- (New York State College of Veterinary Medicine at Cornelltures, intra- or sub-epidermal separation often occurs, and University), PF was diagnosed in 26 of 9750 dogs betweenclinical signs of an autoimmune blistering skin disease 1975 and 1984. This proportion results in an estimatedusually develop.1 In the last 30 years, the identification of incidence of PF of approximately three per 1000 canineantigens targeted by circulating autoantibodies has helped patients referred for skin diseases per year.6 In anotherreshape the classification of autoimmune blistering skin institution (Michigan State University College of Veterinarydiseases in humans. Based on clinical signs, histopathology Medicine), PF was the diagnosis made in 1% of surgicaland immunological characteristics, several entities are now skin biopsies read by veterinary pathologists (R. W.well recognized. For example, the most common diseases Dunstan, personal communication, WSAVA meeting, 1997).associated with autoantibodies against epidermal basement Finally, in a retrospective study of 84 dogs with auto -membrane antigens are bullous pemphigoid (target: collagen immune skin diseases, PF was the diagnosis given toXVII), mucous membrane pemphigoid (laminin-5, collagen 26 subjects, nearly one third of all dogs with autoimmuneXVII, integrin alpha-6 beta-4) and epidermolysis bullosa skin diseases.17© 2006 The Author. Journal compilation © 2006 European Society of Veterinary Dermatology. 17; 291–305 291
  2. 2. Olivry From data published in one article, the incidence of studies found that PF could affect both very young (lessfeline and equine PF could be calculated as five and 10 per than 6 months) and ageing horses of up to 25 years old.6,11,121000 patients per 10 years, respectively.6 Pemphigus Finally, there are too few cases of caprine PF for assem-foliaceus is too rare in goats to estimate its prevalence and bling relevant information on breed, sex and age predis-incidence. position to disease development.Signalment Triggering factors for PFGenetic factors are likely to predispose to the development Environmental factors are suspected to induce flares ofof canine PF. Indeed, data gathered from several studies canine PF. One of such factors may be sunlight exposure.suggest that PF is more frequently diagnosed in dogs from A decade ago, a book chapter reported a seasonal exacer-certain breeds. For example, in one group of 37 dogs with bation of the disease with more active flares and requirementPF, six breeds (bearded collie, Akita, Newfoundland, for higher immunosuppressive drug dosages in warmerSchipperke, Doberman and Finnish Spitz) exhibited a sig- months, but evidence to support such claims unfortunatelynificant risk to develop the trait compared to the control was not provided.20 In contrast to this assertion, a seasonalpopulation.5 However, only two of these breeds (Dobermans pattern of PF development was not found in an epidemio-and Akitas) had more than one representative affected, logical study regrouping 66 dogs with PF.21 More recently,and both breeds exhibited a high odds ratio (OR) to develop Japanese investigators reported that lesional scores of PFPF (OR = 29).5 In a second group of 26 dogs,6 Akitas and worsened in the summer in 10/12 dogs studied, while valuesdachshunds were the only breeds with more than one improved in the winter.22 Experimentally, irradiation ofindividual diagnosed with PF. For dogs reported in this nonlesional skin from a dog with facial-predominant super-article, we calculated the OR for PF development in Akitas ficial pemphigus with 45–90 kJ m−2 of ultraviolet B (UVB)to be 3.0 with a large confidence interval (0.7–12.9).6 Using led to epidermal acantholysis after 1 day. In vitro, incuba-data from the University of Pennsylvania Veterinary Hos- tion of pemphigus serum on UVB-irradiated skin explantspital, breeds at significant risk of PF development included resulted in more intense intragranular acantholysis than onAkitas (OR = 38; 95% confidence interval: 13 – 99), English non-irradiated cell cultures.23 The latter findings suggestcocker spaniels (21; 8–88), chows (12; 4 – 49), shar-peis (8; that additional studies on UV exacerbation of canine2–30) and collies (4; 2–14). Finally, in a University surgical superficial pemphigus are warranted.pathology service, three breeds of dogs accounted for one In horses with PF, a higher risk for flares during fall andthird of all cases of PF, and OR for the diagnosis of PF were winter months was reported in one study,12 but a clear23, 16 and 7 in Akitas, chows and Australian shepherds, seasonal pattern was not observed in the second series ofrespectively (R. W. Dunstan, personal communication, cases.11 In two of these 15 horses, however, signs wereWSAVA meeting, 1997). Interestingly, two female Shetland observed to recur each summer.11sheepdog littermates were reported to develop PF simul- A higher incidence of PF in dogs with allergic skin dis-taneously at 6 months of age.18 In summary, over the years eases has been mentioned, but evidence supporting suchand in various geographical locations in the USA, chows an association was not given.20 Interestingly, a previousand Akitas appear to be at high risk to develop PF. This history of flea allergy dermatitis was the most commoncommon predisposition may not be surprising in light of skin disease reported in dogs later diagnosed with PF inthe recent discovery that these two breeds exhibit closely one study from California.21 This observation must berelated genotypes and are in close phylogenetic linkage.19 taken with caution because of the high prevalence of flea In the three largest case series of dogs with PF, the allergy dermatitis in that particular geographical location.male to female sex ratios were 13:24 (0.5), 14:12 (1.2) and In humans, several drugs are suspected to either cause46:45 (1.0), and these proportions suggest that a sex pre- ‘pharmacological’ acantholysis (i.e. drug-induced pemphigus)disposition is unlikely to occur in this species.5 –7 In these while others can stimulate disease flares in patients alreadyreports, the age of onset of canine PF was very variable, predisposed to develop this illness (i.e. drug-triggeredas it ranged from less than one up to 16 years (means: 4.2, pemphigus).24 Cases of drug-related PF have been sus-6 and 6 years).5 –7 pected in several dogs and rare cats for 20 years.9,25–29 A A breed predisposition for PF has not been reported recent paper provided information on four additionaldefinitively in the feline species even though domestic patients.30 In these four dogs, the diagnosis of drug-relatedshort-haired cats were found to be most commonly affected PF was based on history, clinical signs, histopathology andwith this disease in two case series.6,9 The male to female response to withdrawal of suspected causative drug(s). Insex ratios were 5:5 and 27:30, suggesting that a sex this paper, however, one subject (case 1) was treated withpredisposition for development of PF in cats also was immunosuppressive doses of prednisolone and azathioprineunlikely.6,9 In these two studies, the age of onset of feline for 7.5 months, another (case 2) was given high dosagesPF ranged from less than 1 to 9 and 17 years, respectively of prednisolone for 8.5 months, the last patient received(medians: 5 years).6,9 low dosages of prednisone for 7 months, whereas case 3 In the first study of equine PF, Appaloosas accounted for was not treated with anti-inflammatory medications.30 Inone third of the patients, a proportion five times higher that report therefore two of four patients needed monthsthan that of the general equine hospital population.6 How- of immunosuppression to maintain remission before allever, such breed predisposition was not confirmed in the drugs were discontinued. While one cannot discount theother two case series.11,12 In none of these three papers authors’ hypothesis that their patients were affected withwas a sex predisposition apparent.6,11,12 While no article drug-related pemphigus, one cannot disprove the contra-reported an age predilection for disease development, all hypothesis either. Indeed, it is conceivable that the animals292 © 2006 The Author. Journal compilation © 2006 European Society of Veterinary Dermatology.
  3. 3. Superficial pemphigus in domestic animalsmentioned above could have suffered from natural auto-immune PF that went into prolonged remission after immu-nosuppression was discontinued, as has been shownrecently in several dogs with PF.31 To evaluate the probability of association between theadministration of a medication and the development of aparticular event, an assessment of likelihood of drug re-action must be made using ‘adverse drug reaction probabilityscales’ such as the one developed years ago by Naranjoet al.32 When this scale is applied to all previous cases ofputative drug-related pemphigus in dogs and cats25–30 onlylow scores interpreted as ‘possible’ probabilities of drugreaction are obtained. Therefore, at this time, the strengthof evidence supporting drug causation for rare cases of PFin dogs and cats is weak at best, and further documenta- Figure 2. Canine facial PF. A 3-year-old Australian shepherd withtion of canine and feline cases with highly probable drug- erythema, erosions, scaling and crusting at the time of initialrelated PF is critically needed. presentation to the dermatologist (left). Treatment with niacinamide and tetracycline and intermittent oral prednisone led to minimalClinical signs remission with occasional recurrence of signs (right). During diseaseClinical signs of PF appear to be similar across domestic flares, superficial pustules (top right; arrowheads) evolved rapidly intoanimal species. In most dogs, lesions initially appear on crusts overlying erosions (bottom right).the face, principally on the dorsal muzzle, planum nasale,periocular skin and ears.5,6 In these areas, the pattern usu-ally is strikingly bilateral and symmetrical (Fig. 1).5 In thelargest case series, lesions were restricted to the face in15 of 91 dogs (16%) (Fig. 2).7 In rare canine patients, thedermatosis exhibits a generalized distribution from theonset, but in most cases, lesions will develop towardsregionalization (Fig. 3) or generalization (Fig. 4) over 3 to 12months.5,7 In the largest retrospective study, generalizedskin lesions were present in 60/91 dogs (66%), and inthese dogs, crusts were most prevalent on the trunk (58%).7A remarkable finding of canine PF is the predilection oflesions for the footpads (Fig. 5).5 Indeed, footpad involve- Figure 3. Canine PF (same dog as Figure 1). Skin lesions initially appeared on the face (Figure 1), however, within one week of hair clipping for cruciate ligament repair surgery and following intense sun exposure, PF lesions (pustules, erosions and crusts) erupted on the lateral aspect of the leg where hair had been clipped. Remarkably, there were no lesions on the medial thigh, an area that had been clipped also. ment is seen in one third of dogs with PF,7 and rare canine patients exhibit lesions restricted solely to this location (Fig. 5; right).6,7,33–36 Of note is that mucosal lesions areFigure 1. Canine PF. A 2-year-old chow crossbred dog exhibits crust- only rarely seen in dogs with PF (2/91; 2%).7 Pemphigusing and erosions bilaterally and symmetrically distributed on the dorsal foliaceus confined to the claws has been observed in onemuzzle, dorsal nasal planum and periocular areas. dog.37© 2006 The Author. Journal compilation © 2006 European Society of Veterinary Dermatology. 293
  4. 4. OlivryFigure 4. Canine PF. This 3-year-old English bulldog was affectedwith lesions that progressed rapidly from the face to cover most of thebody surface. Inset: details of rapidly drying pustules and crusts fromthe lateral thigh. Figure 6. Canine PF. Large, grouped and often coalescing superficial pustules exhibit a peripheral erythematous halo. Multiple hair shafts protrude from the roof of the pustule (case material: University of California Davis). The nature of skin lesions is comparable in most dogswith PF: transient pustules evolve rapidly into erosionsand crusts, the latter being the lesions most commonlyseen.5–7 The pustules of PF are usually large and confluent(Fig. 6), and they often exhibit polycyclic borders. Manyhair shafts can protrude from these pustules, in contrastto the lesions of bacterial folliculitis where only a singlehair can be seen coming from each pustule.38 On rareoccasions, pustules, erosions and crusts are grouped ina unique annular, or polycyclic pattern (Fig. 7).5,39 Alopeciaand generalized exfoliative erythroderma are seenoccasionally.5 Pruritus is present in one fourth to onehalf of dogs with PF,5 whereas systemic symptoms con-sisting of anorexia, depression, fever and weight loss areencountered usually in dogs with widespread erosivelesions.6 The clinical signs of feline PF are reminiscent of thoseseen in dogs with this disease. Pustules are extremelytransient, however, and the phenotype is dominated by Figure 7. Canine PF. Crusts overlie erosions with an erythematouserosions and yellowish crusts on the face (Fig. 8), ears border in a grouped polycyclic arrangement.(Fig. 9), and on the feet.6,8,9,40 Pedal lesions, consisting ofsuppuration or crusts, can be seen on or around the foot-pads or ungual folds of claws (Fig. 10).6,8,9,35,40 The pheno- Horses with PF usually are presented with multifocal totype of feline PF is usually mild and fairly localized, but generalized crusting, scaling and alopecia affecting thegeneralized lesions can be seen also.9 The distribution of face, neck, trunk and extremities (Fig. 11).6,11,12 Pustuleslesions of feline PF is usually bilateral and symmetrical.9 are observed rarely, and whenever present, they are Figure 5. Canine PF. Footpad lesions of canine PF vary with their chronicity. Acute lesions (left) consist of pustules (arrowheads; same dog as in Figure 4), erosions and crusts. With time, crusts coalesce (middle) and dry to form fissures (right).294 © 2006 The Author. Journal compilation © 2006 European Society of Veterinary Dermatology.
  5. 5. Superficial pemphigus in domestic animalsFigure 8. Feline PF. Alopecia, erosions and crusts developed on theface of a 1.5-year-old Siamese cat during a flare of PF (courtesy ofDr Barbara Atlee). Figure 11. Equine PF. A 12-year-old quarterhorse mare exhibits erosions and crusts in a figurate pattern on the face and neck (case material from the University of California Davis).Figure 9. Feline PF. Yellowish crusts are present on the convex (left)or concave aspects of the pinnae of two cats with PF (left: courtesyof Dr Barbara Atlee; right: case material from the University ofCalifornia Davis). Figure 12. Canine PF. Aspiration cytology from the content of a superficial pustule reveals numerous neutrophils, some eosinophils and scattered isolated or grouped acantholytic keratinocytes (Diff–Quick). In goats, pustules, crusts, scales and alopecia predominate on the face, ventral abdomen, limbs, perineum and tail. In female animals, lesions may affect the udder and teats.13 –16 Pemphigus foliaceus in animals has been reported inFigure 10. Feline PF. Crusting can be seen around footpads and association with systemic diseases such as hypothyroidism,42claws (left) or on pads themselves (right). leishmaniasis,43 thymoma44 and systemic lupus erythema- tosus.45 The relationship between PF and these entities may be coincidental, or it could reflect a systemic diseasetransient.6,11,12 Skin lesions may exhibit a unique annular process leading to the induction of immunological imbal-pattern as in dogs.41 Remarkably, ventral oedema is seen ances and development of anti-keratinocyte many horses with PF.12 Systemic symptoms, such asdepression and lethargy, were noticed in 50% of horses Cytologywith PF in one study6 but a similar observation was not The diagnosis of PF in animals commences with themade in another retrospective study.11 Lesions of equine demonstration of acantholytic keratinocytes in impressionPF are occasionally painful and /or pruritic.11,12 smears of intact pustules (Fig. 12).5–7 Indeed, isolated to© 2006 The Author. Journal compilation © 2006 European Society of Veterinary Dermatology. 295
  6. 6. OlivryFigure 13. Canine (left) and feline (right) PF. In these early microscopic lesions, fluid-filled vesico-pustules contain few neutrophils and acantholytickeratinocytes. The sample on the right was obtained as a shave biopsy from an auricular lesion not existing 2 h before (haematoxylin and eosin).clustered (e.g. ‘rafts’) free-floating rounded keratinocytesadmixed with nondegenerated neutrophils and rarer eosi-nophils are seen usually.5–7 Acantholytic keratinocytesexhibit either microscopic characteristics of normal differ-entiated spinous or granular layer epithelial cells, or theypresent signs of apoptosis with eosinophilic cytoplasm,condensed chromatin or karyorrhexis. Occasionally, neu-trophils can be seen in close apposition to detached kerat-inocytes. The presence of acantholytic keratinocytes andneutrophils is not specific of PF, however. Similar micro-scopical findings have been found in canine and equinecases of pustular dermatophytosis, a PF mimicker inwhich Trichophyton fungi invade the stratum corneum andinduce subcorneal acantholytic neutrophilic pustules.46 – 48Keratinocyte acantholysis has been reported also in dogs Figure 14. Canine PF. Intraepidermal vesico-pustule in the granularwith bacterial skin infections.38 layer of footpad epidermis (haematoxylin and eosin).HistopathologyIn dogs, cats, horses and goats with PF, histological exam-ination of lesional skin reveals similar findings. Very earlylesions may be vesicles with acantholytic keratinocytesand scarce neutrophils (Fig. 13). However, these lesionsrapidly evolve into intragranular (Fig. 14) or subcornealpustules (Figs 13,14,15) with isolated and /or clusteredacantholytic cells.5,6,38,39 In these lesions, neutrophils pre-dominate, but variable numbers of eosinophils may befound.5–7,38,39 Pustules commonly invade the epitheliumand /or the lumen of the follicular infundibulum.5,38 In gen-eral, the pustules are large and span the length of multiplefollicular units, a finding that differentiates these lesionsfrom those of bacterial folliculitis.12,38 Similarly, recornifica-tion, defined as newly reformed stratum corneum at the Figure 15. Canine PF. Intraepidermal to subcorneal neutrophilicbase of neutrophilic pustules, is more suggestive of PF and eosinophilic pustule with single and clustered acantholytic(Fig. 16) than bacterial folliculitis.38 Microscopic character- keratinocytes. Of interest is the ‘keratin filament ring’ that can beistics of acantholytic keratinocytes mirror those observed seen in acantholytic or pre-acantholytic keratinocytes (arrowheads) from the presumed detachment of keratin filaments fromwith cytology. Epidermal cells that recently detached from desmosomes (haematoxylin and eosin).their neighbours usually appear similar to differentiatedkeratinocytes whilst other cells exhibit cytological charac-teristics of apoptosis.5 Apoptotic keratinocytes are seen apoptosis may reflect the phenomenon of anoikis that fol-often in the epidermis of dogs with PF,49 and as a result lows the rupture of desmosomal cadherin adhesion duringthese apoptotic epidermal cells cannot be taken for bona acantholysis.50 Alternatively, activation of the apoptoticfide markers of underlying drug reactions. The induction of pathway could be an early consequence of the binding of296 © 2006 The Author. Journal compilation © 2006 European Society of Veterinary Dermatology.
  7. 7. Superficial pemphigus in domestic animalsFigure 16. Feline PF. Large subcorneal neutrophilic acantholytic pustule Figure 17. Canine PF. Direct IF performed on a frozen skin sectionwith underlying epidermal recornification (haematoxylin and eosin). reveals intercellular epidermal IgG in the stratum spinosum and granulosum (anticanine IgG fluorescein).autoantibodies to keratinocytes as shown recently in humans nique was deemed unreliable for the diagnosis of animalwith pemphigus.51 Even though acantholytic keratinoc- pemphigus, as circulating IgG autoantibodies rarely wereytes can be seen in pyogenic skin bacterial infections38 found in canine, feline or equine sera.6,39 When antikerat-and pustular dermatophytoses,46– 48 the presence of a inocyte antibodies were detected in canine PF sera, thehigh number of free-floating epidermal cells, often seen in titre was usually inferior to 1 : 40.5,6 A recent study pro-clusters, may be more suggestive of PF than other infec- vided information suggesting that indirect IF results willtious dermatoses.38 vary according to the substrate utilized for autoantibody In one study, immunostaining for desmogleins was detection. When normal bovine oesophagus substratealtered in skin biopsies of dogs with PF compared to those was used, circulating antibodies were detected in 65% ofof normal individuals.52 In canine PF skin, desmoglein affected patients.55 Similarly, indirect IF was positive for allstaining appeared as distinct clumped deposits at the canine PF sera tested on cultured canine keratinocytes.56,57periphery of keratinocytes and /or dark cytoplasmic stain- When other epidermal substrates were employed, how-ing of acantholytic cells consistent with internalization of ever, the frequency of detection of circulating autoantibodiesthese molecules.52 was usually lower.55 Unfortunately, the skin of the nasal planum exhibits ‘physiological’ intercellular IgG, renderingImmunopathology indirect IF testing positive using this substrate and normal dog sera.55 At North Carolina State University, indirect IFDirect immunofluorescence testing performed using normal canine footpad revealedDirect immunofluorescence (IF) or immunoperoxidase antikeratinocyte autoantibody titres superior to 1 : 50 inhave been used to detect antikeratinocyte autoantibodies the serum of 73 of 87 dogs with PF (84%).58 Using thisdeposited in vivo in the skin of animals with PF. Skin-fixed substrate, nearly half of canine PF sera tested wereintercellular epidermal IgGs were found in most cats, shown to contain IgG that bound to keratinocytes of bothhorses and goats with PF.6,15 Similarly, intercellular epider- stratum spinosum and granulosum, but additional IFmal IgG autoantibodies were detected in 66 – 80% of patterns also were uncovered.58 These results providedcanine specimens examined (Fig. 17).5,6,17,39,53 One study evidence of immunological heterogeneity of canine PF.58established that, in some dogs with PF, skin-fixed auto- Using neonatal mouse skin as substrates, canine PFantibodies belonged to IgG2 and/or IgG4 subclasses.54 In rare serum autoantibodies were detected in 36 of 44 dogs withinstances, intercellular deposits of IgA or IgM and activated PF (82%) (Fig. 18), and they were found to be of eithercomplement (C3 fraction) were observed.6,39 In one third IgG1 (30/44; 68%) or IgG4 (35/44; 80%) isotypes.59 Similarof canine specimens, intercellular fluorescence was findings were reported by other investigators.22 In sixrestricted to the upper half of the epithelium.5 In some dogs, immunosuppression led to a reduction in clinicaldogs with PF, direct IF testing of skin biopsy specimens scores with serum IgG, IgG1 and IgG4 autoantibody titreshas remained negative, and these results were attributed decreasing in four, one and four patients, respectively.59to glucocorticoid therapy administered prior to specimen Similarly, serum titres of IgG autoantibodies correlatedcollection.6 Unfortunately, intercellular epidermal IgG also with the severity of clinical signs of canine PF in twocan be found in biopsy specimens obtained from dogs with recent reports from the same group.22,60dermatoses other than PF.6,17 These findings markedly Finally, in one retrospective study, indirect IF testingreduce the specificity of direct IF testing for the diagnosis revealed circulating antikeratinocyte autoantibodies in 0/9of canine PF. (0%) and 5/9 (56%) cats and horses with PF, respectively.6Indirect immunofluorescence Advanced immunological testsThe identification of circulating pemphigus autoantibodies Unfortunately, at this time, studies investigating the nature ofhas been performed historically by means of indirect IF autoantigens and pathogenicity of circulating autoantibodiestesting of the animal’s sera. For many years, this tech- of feline, equine and caprine PF have not been reported.© 2006 The Author. Journal compilation © 2006 European Society of Veterinary Dermatology. 297
  8. 8. Olivry Figure 19. Canine PF. Only rare sera from dogs with PF recognize canine dsg1 expressed ectopically on the surface of transfected 293T human kidney cells. These results indicate that dsg1 is only a minor antigen in dogs with PF (indirect IF, anticanine IgG-fluorescein).66 contrary to previous beliefs, dsg1 appears to be only a minor autoantigen for canine PF. A second desmosomal cadherin, desmocollin-1, was pursued as a tentative autoantigen for PF in dogs. CanineFigure 18. Canine PF. Serum IgG recognize antigen(s) present on the desmocollin-1 was cloned, sequenced and producedmembrane of superficial epidermal keratinocytes (arrowheads), and ectopically in transiently transfected Chinese hamsteralso, in some patients, in the cytoplasm of basal and follicular ovary cells.67 Unfortunately, sera from six dogs with PF didkeratinocytes (arrows, bottom) (indirect IF, neonatal mouse skin not recognize canine desmocollin-1 isolated from trans-substrate).59 fected cells using immunoprecipitation–immunoblotting.67 Finally, two recent studies provided additional informa- tion relevant to the localization of putative canine PF anti- In contrast, the search for canine PF autoantigens has gen(s). In one dog with nondsg1-specific antikeratinocytebeen ongoing for over 15 years. Limited immunoblotting autoantibodies, post-embedding immunoelectron micros-studies first revealed that serum IgG autoantibodies from copy confirmed the binding of IgG to the extracellular sec-two of two dogs with PF bound to a 148 kDa antigen tion of desmosomes.65 Finally, whatever the autoantigensextracted from lip epithelium.61 In another study, autoanti- are, there is evidence for pathogenicity of canine PF IgG.bodies from eight of 16 dogs were found to bind a 160 kDa Indeed, the intradermal injection into neonatal mouse skinprotein extracted from cultured normal canine keratinoc- of IgG isolated from the serum of three dogs with PF ledytes.56,62 This 160 kDa antigen was identified also by the to acantholytic blistering below the stratum granulosumserum of a human patient with PF.56 At first, these 148 and (Fig. 20).68 Remarkably, acantholysis occurred in the160 kDa antigens were suspected to represent different absence of neutrophil granulocytes in the vesicles.glycosylation states of canine desmoglein-1 (dsg1), the In summary, at the time of this writing, the identity ofhomologue of the major PF antigen in humans. major canine PF antigen(s) remains unknown. The identi- From the late 1990s to mid-2000s, numerous attempts fication of these antigen(s) may lead to a more precisewere made to determine whether dsg1 was, indeed, the reclassification of superficial pemphigus in dogs based onmain antigen in dogs with PF. The canine dsg1 gene was clinical, histopathological and immunological knowledge.cloned and sequenced, and it was found to encode apeptide of 1055 amino acid identical in organization to the Treatment and outcomehuman and bovine genes with highest homology existing To date, immune suppression remains the initial therapeu-in the sequences of the aminoterminal EC1 and EC2 tic intervention of choice for PF in domestic animals. Ofsegments.63 The extracellular segment of canine dsg1 note is that all recommendations for immunosuppressionwas produced using the baculovirus expression system.64 initially were based on interventions used for treatment ofRemarkably, this recombinant protein was recognized by the human disease, and prospective clinical trials were notsera from human patients with PF, but it was not identified performed to optimize protocols for animals. As a result,by IgG from any of the canine PF sera tested.62,65 information in the following paragraphs was collated almost Recently, human 293T kidney cells were transfected to exclusively from retrospective case series. Historically,express ectopically membrane-bound canine dsg1. Indirect standard-of-care treatment of canine PF relied on theIF staining established that only five of 83 canine PF sera induction of immunosuppression with oral glucocorticoids,(6%) recognized canine dsg1-transfected human cells such as prednisone or prednisolone, at daily dosages var-(Fig. 19).66 When present, antidsg1 IgG autoantibodies ying from 2 to 6.6 mg kg−1 divided in one or two adminis-were found to target calcium and glycosylation-dependent trations.5–7,69 If lesions decreased in extent and severityepitopes.66 In summary, at the time of this writing and in with this regimen, then the dose and /or administration298 © 2006 The Author. Journal compilation © 2006 European Society of Veterinary Dermatology.
  9. 9. Superficial pemphigus in domestic animals More recently, 43 dogs with PF were seen at the Uni- versity of Pennsylvania between 1994 and 2000.73 Of these patients, only 17 of 43 subjects (40%) were still alive at the end of the study period. Most dogs died during the first year of treatment. Of the dogs that died, 18 of 26 (69%) were euthanized because of lack of response of lesions to therapy, poor quality of life or adverse effects of treat- ment.73 Interestingly, the addition of antibiotics during the induction of immunosuppression was associated with a significant improvement in survival rate in this cohort of patients.73 In contrast to such results that suggest a poor outcome following ‘standard-of-care’ therapy with combined oral immunosuppression, Rosenkrantz reported a 71% survivalFigure 20. Canine PF. The intradermal injection of IgG from dogs with rate after one year in 31 dogs with PF with only four dogsPF into neonatal mouse skin results in subgranular blister formation, euthanized because of poor response to therapy or treat-thereby confirming the pathogenicity of serum autoantibodies ment discontinuation with subsequent relapses.69 Similarly,(haematoxylin and eosin).68 the latest series of 91 dogs with PF reported by Mueller and colleagues provided additional data on favourable treatment outcome.7 Of 88 dogs treated for PF, 46 under-frequency of glucocorticoids was reduced with the goal of went complete remission (52%), 31 (35%) achievedrapidly achieving alternate day intake.5,69 In many canine partial remission of lesions, and only 11 (13%) were euth-patients, however, glucocorticoid therapy alone appears anized.7 Reasons for euthanasia included lack of responseincapable in halting or slowing the progression of skin to treatment (4/11; 36%), unacceptable side-effects oflesions.5 In these cases, cytotoxic drugs are usually medications used (2/11; 18%) and unrelated or unknownadded.5,6,69 Azathioprine (2–2.5 mg kg−1, orally, once daily), causes.7 Complete remission was achieved with oral glu-cyclophosphamide (25 mg m−2, orally, once daily) or chlo- cocorticoids in 15 of 39 dogs (38%) within 1.5–12 monthsrambucil (0.2 mg kg−1 every 24 – 48 h) have been proposed of treatment initiation (average: 7 months), and this occurredas adjunct cytotoxic drugs.5,6,69 Alternatively, immune modu- with a glucocorticoid–azathioprine combination in 18 of 33lation with injectable aurothioglucose (1 mg kg−1 week−1) dogs (55%) within 2–29 months (average: 12 months) ofwas used two decades ago to treat dogs with unacceptable starting therapy. Therefore, the addition of azathioprine didside-effects of immune suppressive medications.5,6 not lead to a significant difference in the time needed toFinally, rare dogs with PF exhibit lesions that respond to achieve remission compared to the use of glucocorticoidstetracycline and niacinamide (250–500 mg of each, three alone.7 In five dogs, however, the sole administration oftimes daily).7,70 prednisolone was unsuccessful, and the addition of azathi- In recent years, two small prospective open clinical trials oprine led to complete lesion remission.7 Remarkably,explored the efficacy of novel drugs for treatment of dogs adverse drug events occurred significantly more often withwith PF. In a 16-week pilot study, eight subjects were prednisolone–azathioprine combination than glucocorticoidstreated with mycophenolate mofetil at 20 – 40 mg kg−1 per alone. These observations suggest that a prospectiveday, divided in three daily doses.71 In three dogs, a reduc- study must be undertaken to determine whether or nottion of lesional area and /or severity were seen. Four subjects the addition of azathioprine offers any benefit to glucocor-did not complete the study and two were euthanized. ticoid monotherapy in dogs with PF.Additionally, all dogs required concurrent glucocorticoid In this series of dogs with PF, there were no significanttherapy to control the severity of skin lesions.71 As a result differences in either rate of complete remission or deathof high cost and limited proven benefit, there is currently between dogs with facial localized vs. generalized lesions,insufficient evidence for recommending this drug for treat- dogs treated with prednisolone alone vs. prednisolone andment of canine PF. azathioprine combination, or dogs treated with immuno- Recently, a small pilot study evaluating the efficacy of suppression with or without antibiotics.7 In summary, theoral cyclosporin (5 –10 mg kg−1 once daily) in five dogs with review of treatment outcome in this cohort of dogs withPF was reported.72 Four dogs did not complete the trial PF suggests that the benefit of azathioprine addition tobecause of perceived lack of efficacy. In one dog, there was oral glucocorticoid regimens must be weighed carefullya transient reduction in lesional scores.72 Future studies against the cost of treatment monitoring and additionalshould evaluate whether this drug could be used as a risk to patients.glucocorticoid-sparing agent, or whether higher dosages Finally, the persistence of long-term remission of canineare needed to induce lesion remission. PF after discontinuation of immunomodulating therapy The treatment outcome of canine PF appears to be has been reported in 7–22% of dogs with PF.31 Similarvariable, presumably because of variations in treatment results were obtained in two of 88 dogs (2%) in the mostprotocols and /or disease subtypes. In articles describing recent case series. 7cases seen in the 1970s and 1980s, 18 of 34 (53%)5 and In cats with PF, glucocorticoid monotherapy usually is23 of 26 (88%) dogs with PF6 were reported to have been effective for achieving clinical remission. Historically, the‘managed successfully’ with the interventions mentioned oral glucocorticoids of choice have been prednisone (4–above. 5 mg kg−1 daily) and triamcinolone (0.6–2 mg kg−1 daily).9© 2006 The Author. Journal compilation © 2006 European Society of Veterinary Dermatology. 299
  10. 10. OlivryRecent pharmacological data, however, have shown that human cicatricial pemphigoid within the spectrum oforal prednisone is not very well absorbed and /or con- ‘mucous membrane pemphigoid’.80 Whether feline, equineverted into prednisolone in cats, therefore suggesting that and caprine PF are immunologically heterogeneous cur-oral prednisolone is a better choice than prednisone in this rently remains unknown.species.74 In cats whose PF lesions fail to respond to glu- As a result, and until further studies allow a refinementcocorticoids, chlorambucil (0.2 mg kg−1, orally, once daily) in the nosology of this syndrome, we propose that theis the cytotoxic drug most commonly used.9,75 Even though diagnosis of PF be based principally on clinico-pathologicalazathioprine has been used successfully to treat cats with grounds. Therefore, it is suggested that, at this time, thePF40 this drug is no longer used widely as it is known to diagnosis of PF be given to animals that suffer from a skincause profound neutropenia and thrombocytopenia in disease satisfying ALL three criteria below:feline patients.76 This abnormal sensitivity to azathioprinemay be due to their recently discovered lower activity of 1 Clinical examination: pustules rapidly evolving inthiopurine methyltransferase, an enzyme that metabolizes shallow erosions and crusts with predominance toazathioprine and whose deficiency can cause severe the face and feetmyelosuppression.77,78 Sometimes, lesions of feline PF 2 Histopathology: superficial epidermal or follicularrespond to aurothioglucose.6 pustules rich in neutrophils and often-clustered In one study, complete remission of PF lesions occurred acantholytic keratinocytesin 15 of 15 cats (100%) using triamcinolone alone, in eight 3 Differential diagnoses: rule out of other acantholyticof 13 (62%) using prednisone alone, and in nine of 11 neutrophilic pustular diseases, especially exfoliatin-(82%) using a prednisone/chlorambucil combination.9 In associated staphylococcal pyodermas and pustularthat series of cases, cats receiving triamcinolone exhibited dermatophytosis due to corneophilic dermatophytes.a higher rate of complete remission and a lower rate ofadverse drug events than those receiving a prednisone/chlorambucil combination.9 Only four of 30 cats (13%) for Pemphigus erythematosuswhich long-term treatment outcome was known were In humans, PE is a controversial clinically heterogeneouseuthanized because of their disease or to treatment com- entity that has been historically linked to both discoidplications.9 In an older series of 10 cats with PF, treatment lupus erythematosus (DLE) and superficial pemphigus.81with prednisolone was reported to be effective in six subjects Supporting the current concept that human PE in fact rep-(60%) and with aurothioglucose in four patients (40%).6 resents a variant of PF, immunological investigations have Similarly to dogs and cats with this disease, lesions of confirmed the identity of the main human PE autoantigenPF can be treated successfully in horses and goats with as dsg1, the major PF antigen.82,83 Additionally, serumeither prednisolone or dexamethasone alone or in combi- autoantibodies targeting the basement membrane zonenation with aurothioglucose.6,12,15 As is seen in cats, pred- antigens bullous pemphigoid antigen 1 (230 kDa) and peri-nisone may be of limited efficacy in horses due to its poor plakin (190 kDa) have been identified in rare patients.83absorption and/or biotransformation into prednisolone.79 The first mention of the existence of PE in animals wasIn one of the retrospective studies, five of 13 horses in a general review article of immunological skin diseases(38%) were euthanized for either lack of response of by Scott in 1978.84 Two years later, the same author includedlesions to treatment or development of steroid-induced previously reported cases in an article describing clinical,acute laminitis.12 Four of 11 horses (36%) remained in histopathological and immunological characteristics ofremission for more than one year after immunosuppres- four dogs and one cat with PE.85 In June 2006, the searchsion lasting from three to 12 months was discontinued.12 of several reference databases identified – in addition toIn the second study, follow-up information was reported the original princeps descriptions – only one case series offor seven of 15 horses.11 Only one subject was euthanized nine dogs6 and scattered case reports of canine39,86– 90due to financial constraints, while the other horses achieved and feline PE.91remission with prednisone, prednisolone or aurothioglu- In the largest case series, PE was reported to be thecose.11 In one horse, long-term remission was maintained third most common form of pemphigus seen at Cornellin the absence of treatment.11 Of note is that none of the University Veterinary Teaching Hospital, yet patients withthree published case series provided information substan- PE only accounted for less than one of 1000 dogs and catstiating the previously held belief that equine PF is of better presented with skin diseases over 10 years.6 Unfortunately,prognosis in young horses than in old subjects. due to the scarcity of information on canine and feline PE, detailed information on any breed, age and sex predispo-Conclusions: diagnosing pemphigus foliaceus in sition for this disease cannot be provided.domestic animals Clinically, dogs and cats with PE are reported to presentIn summary, at the time of this writing (June 2006), it is with pustules erosions and crusts localized to the faceapparent that canine PF appears to be clinically, histologi- and pinnae along with depigmentation, erythema andcally and immunologically heterogeneous with only rare erosion/ulceration of the nasal planum and dorsal muzzlepatients having autoantibodies targeting dsg1, the canine (Fig. 21).6,39,85–91 Only rare patients exhibit nonfacial lesions.6homologue of the major human PF antigen. It is likely Microscopic examination of skin biopsies of dogs and catstherefore that the entity currently called ‘canine PF’ may with PE reveals intragranular to subcorneal neutrophilicnot be a single disease, but a clinicopathological syndrome and eosinophilic acantholytic pustules suggestive of PFregrouping several immunological variants. In many ways, along with a lichenoid interface dermatitis that resemblesthis situation is similar to the recent reclassification of that of DLE.6,39,85–91300 © 2006 The Author. Journal compilation © 2006 European Society of Veterinary Dermatology.
  11. 11. Superficial pemphigus in domestic animalsFigure 21. canine ‘PE’. A 2-year-old colliepresented with a pustular, erosive andcrusting dermatosis bilaterally andsymmetrically distributed to the face (left)and ears. Additionally, there weredepigmenting atrophic scars, erosions andcrusts on the dorsal nasal planum (right,top) as well as depigmentation, scarringand deep erosions/ulcers on the ventralnares (right, middle and bottom).Histological and immunologicalcharacteristics resembled those previouslyreported for canine PE. On direct IF examination, skin biopsy specimens of 3 Superficial acantholytic epidermal pustules are seencanine and feline PE uniquely exhibit both intercellular in both canine PF and PE, while the presence of aepidermal pemphigus-like and basement membrane lichenoid ± interface dermatitis in the latter may onlylupus-like depositions of immunoglobulins with or without reflect the nasal/paranasal location of skin biopsies inactivated complement.6 Of note is that not all dogs with dogs with PE. Indeed, dogs with various nasal derm-PE will have this basement membrane immunoreagent atoses often exhibit a band-like diffuse superficialdeposition.6,85 Indirect IF performed with canine and feline plasmacytic to lymphoplasmacytic dermatitis with orPE sera has remained negative for all patients tested.6,85 without basal cell damage.92In contrast, low serum titres of antinuclear antibodies 4 The observation of immunoglobulins and complement(1 : 10 –1 : 40) have been identified in approximately half at the basement membrane zone by direct IF is notof sera from dogs with PE.6,85 specific for lupus, as it is seen also in canine PF and The treatment outcome of canine and feline PE is numerous other immune-mediated skin diseases.53,93reported to be good, with lesions responding to immuno- Moreover, serum antibasement membrane autoanti-suppressive regimens used to treat patients with PF.6 In bodies can be detected in some dogs with PF.58one of two dogs with PE, the administration of a tetracycline 5 The presence of low serum titres of antinuclear anti-and niacinamide regimen resulted in a partial resolution of bodies in dogs with PE is not unique to this entityclinical signs.70 The use of sun avoidance and sunscreens because of the recent observation that nearly 30% ofhas been advocated.6 Finally, topical treatment with 0.1% dogs with various phenotypes of PF also exhibit lowtacrolimus ointment was reported to be of benefit, as an titres of serum IgG targeting nuclear antigens.58adjunct medication, in two dogs with PE.89 6 Finally, PE cannot be individualized from PF on the In summary, the rare descriptions of canine and feline basis of differing treatment outcomes as a favourablePE published since 1980 have implied that this disease response to treatment is seen both in dogs with PE andrepresented an unusual facial-predominant dermatosis with in canine patients with localized or generalized PF.7clinical, histopathological and immunopathological charac-teristics of both PF and DLE. As a result, the current dogma In summary, at this time, there is insufficient evidenceis that PE might be a crossover between these two entities. supporting that canine PE is markedly different from local- This concept must be considered controversial, how- ized facial PF either clinically, histologically, immunologi-ever. Indeed, the rationale for previous individualization cally or prognostically. Additional studies are needed toof canine PE as an entity distinct from PF needs to be re- determine whether there would be any value – for eitherexamined in light of recent knowledge suggesting that patients or clinicians – in individualizing canine PE as aboth diseases exhibit very similar characteristics: separate entity, whether it should be reclassified as a localized variant of PF, or whether it is a genuine crossover 1 The predominance of skin lesions to the face is not between PF and DLE or other entities. Similarly, there is unique to PE, as facial lesions are identified also in not enough information on feline PE and PF to permit an most dogs with PF, and they are restricted to this area accurate separation between these two diseases. in 16% of canine patients with this disease.7 2 Photosensitivity is not specific for canine PE, as pre- liminary evidence suggests that this phenomenon Panepidermal pustular pemphigus exists also for canine PF (see discussion in the PF In 1994, Wurm, Mattise and Dunstan proposed the crea- section). tion of a new entity named ‘canine panepidermal pustular© 2006 The Author. Journal compilation © 2006 European Society of Veterinary Dermatology. 301
  12. 12. Olivrypemphigus’ to regroup cases previously diagnosed as years of continuous technical support by Stan Dunstonpemphigus vegetans and PE.94 The main criteria for diag- also is acknowledged.nosing canine PPP were the demonstration of neutrophil-rich and eosinophil-rich acantholytic pustules at all layers Referencesof the epidermis and the suprabasal infundibular outer root 1. Fassihi H, Wong T, Wessagowit V et al. Target proteins in inheritedsheath epithelium.94 A considerable morphologic overlap and acquired blistering skin disorders. Clinical and Experimentalbetween PPP and PF in dogs was noted to exist, but the Dermatology 2006; 31: 252–9.main difference between these two entities was the 2. Stannard AA, Gribble DH, Baker BB. A mucocutaneous disease inobservation of pustules in the granular and upper spinous the dog resembling pemphigus vulgaris in man. Journal of thelayers in PF and the occurrence of these lesions through- American Veterinary Medical Association 1975; 166: 575–82.out the epidermis in PPP.94 3. Hurvitz AI, Feldman E. A disease in dogs resembling human pem- phigus vulgaris: case reports. Journal of the American Veterinary The rationale for creating an entity solely based on Medical Association 1975; 166: 585–90.histological grounds is subject to controversy. Indeed, as 4. Halliwell REW, Goldschmidt MH. Pemphigus foliaceus in thenoted above, there is current evidence of clinical, his- canine: a case report and discussion. Journal of the American Ani-topathological and immunological heterogeneity among mal Hospital Association 1977; 13: 431–6.dogs diagnosed with PF, and the individualization of distinct 5. Ihrke PJ, Stannard AA, Ardans AA et al. Pemphigus foliaceus insubsets of canine pemphigus must await the determina- dogs: a review of 37 cases. Journal of the American Veterinary Medical Association 1985; 186: 59–66.tion whether the identification of the various autoantigens 6. Scott DW, Walton DK, Slater MR et al. Immune-mediated derma-targeted provides a rationale for a revision of disease clas- toses in domestic animals: ten years after – Part I. Compendiumsification. Indeed, the observation of microscopic lesions on Continuing Education for the Practicing Veterinarian 1987; 9:arising at different epithelial depth simply could be due to 424–35.variability in distribution of antigens targeted by autoanti- 7. Mueller RS, Krebs I, Power HT et al. Pemphigus foliaceus in 91bodies at different body locations. This concept is best dogs. Journal of the American Animal Hospital Association 2006;illustrated by the recent discovery that, for example, dsg1 42: 189–96. 8. Manning TO, Scott DW, Smith CA et al. Pemphigus diseases incan be detected on keratinocytes of all epidermal layers in the feline: seven case reports and discussion. Journal of thethe dorsal muzzle, pinna and footpads of dogs.95 In contrast, American Animal Hospital Association 1982; 18: 433–43.dsg1 is visible only in the upper layers of canine shoulder, 9. Preziosi DE, Goldschmidt MH, Greek JS et al. Feline pemphigusgroin or abdomen epidermis.95 Therefore, dogs with antidsg1 foliaceus: a retrospective analysis of 57 cases. Veterinary Derma-associated pemphigus would be more likely to exhibit tology 2003; 14: 313–21.superficial lesions on the abdomen and groin and more 10. Johnson ME, Scott DW, Manning TO. A case of pemphigus‘panepidermal’ lesions on the muzzle, ears and footpads. foliaceus in the horse. Equine Practice 1981; 3: 40–5. 11. Zabel S, Mueller RS, Fieseler KV et al. Review of 15 cases of In summary, at the time of this writing, there is little pemphigus foliaceus in horses and a survey of the literature.evidence supporting the separation of canine PPP from the Veterinary Record 2005; 157: 505–9.main superficial pemphigus group (e.g. PF). Further studies 12. Vandenabeele SIJ, White SD, Affolter VK et al. Pemphigus foliaceusare needed to determine whether clinical, treatment in the horse: a retrospective study of 20 cases. Veterinary Derma-outcome and immunological information warrants the tology 2004; 15: 381–8.individualization of PPP as a bona fide entity. 13. Scott DW, Smith MC, Smith CA. Pemphigus foliaceus in a goat. Agri Practice 1984; 5: 38–45. 14. Jackson PGG, Lloyd S, Jeffries AR. Pemphigus foliaceus in aConclusions goat. Veterinary Record 1984; 114: 479. 15. Valdez RA, Gelberg HB, Morin DE et al. Use of corticosteroids andThe last decades have seen the discovery of canine, feline, aurothioglucose in a pygmy goat with pemphigus foliaceus. Journalequine and caprine homologues of superficial pemphigus of the American Veterinary Medical Association 1995; 207: 761– humans. The 1980s and early 1990s saw the separation 16. Pappalardo E, Abramo F, Noli C. Pemphigus foliaceus in a goat.of several subtypes of pemphigus (PF, PE and PPP) Veterinary Dermatology 2002; 13: 331–6. 17. Werner LL, Brown KA, Halliwell REW. Diagnosis of autoimmunebecause of minor differences in gross and microscopic skin disease in the dog: correlation between histopathologic,lesions. However, the recent observation of clinical, histo- direct immunofluorescent and clinical findings. Veterinary Immu-logical or immunological overlap between these three nology and Immunopathology 1983; 5: 47–64.entities and the discovery of marked heterogeneity among 18. Noxon JO, Myers RK. Pemphigus foliaceus in two Shetlanddogs with PF suggests that, until further investigations sheepdog littermates. Journal of the American Veterinary Medicalhave characterized the major autoantigens in this group of Association 1989; 194: 545–6.diseases, there is not enough evidence to warrant individ- 19. Parker HG, Kim LV, Sutter NB et al. Genetic structure of the pure- bred domestic dog. Science 2004; 304: 1160–4.ualizing subsets within the superficial pemphigus group in 20. Rosenkrantz WS. Pemphigus foliaceus. In: Griffin CE, Kwochkaanimals. The terminology of ‘PF’ remains most appropriate KW, MacDonald JM, eds. Current Veterinary Dermatology – theat this time, keeping in mind that this denomination might Science and Art of Therapy. St Louis, MO: Mosby Year Book,represent a syndrome rather than a homogeneous entity. 1993, 141–8. 21. Pascal A, Shiebert J, Ihrke P. Seasonality and environmental risk factors for pemphigus foliaceus in animals: a retrospective studyAcknowledgements and funding of 83 cases presented to the Veterinary Medical Teaching Hospital, University of California Davis from 1976 and 1994 (abstract). Pro-The author is grateful to Drs Gregg Dean, Luis Diaz, Toshiroh ceedings of the American Academy of Veterinary DermatologyIwasaki, Eliane Mueller, Koji Nishifuji, Maja Suter, Simon and American College.of Veterinary Dermatology Annual Meeting.Warren and Zhi Liu for their past and current collaborations Santa Fe, NM: American Academy of Veterinary Dermatology,in the field of canine pemphigus foliaceus research. Twelve 1995: 24–5.302 © 2006 The Author. Journal compilation © 2006 European Society of Veterinary Dermatology.
  13. 13. Superficial pemphigus in domestic animals22. Iwasaki T, Yamakita-Yoshida K. Time course of autoantibodies and association with systemic lupus erythematosus, and subsequent clinical signs in canine pemphigus foliaceus (Abstract). Proceed- lymphoma in a cocker spaniel. Journal of Small Animal Practice ings of the American Academy of Veterinary Dermatology and 2000; 41: 266–70. American College of Veterinary Dermatology Annual Meeting. 46. Scott DW. Marked acantholysis associated with dermatophytosis Monterey, CA: American Academy of Veterinary Dermatology. due to Trichophyton equinum in 2 horses. Veterinary Dermatology 2003, 240. 1994; 5: 105–10.23. Iwasaki T, Maeda Y. The effect of ultraviolet (UV) on the severity 47. Parker WM, Yager JA. Trichophyton dermatophytosis – A disease of canine pemphigus erythematosus (Abstract). Proceedings of easily confused with pemphigus erythematosus. 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Oxford: sensus on mucous membrane pemphigoid: definition, diagnostic Blackwell Publishing, 2002: 30–6.Résumé Chez l’homme, la dénomination pemphigus regroupe un ensemble de dermatoses autoimmunes caractériséespar une séparation intraépidermique résultant d’un détachement cellulaire par acantholyse. Ces entités sont classées ense basant sur la profondeur du clivage épidermique, et des formes superficielles (pemphigus foliacé, pemphigus à IgA) etdes formes profondes (pemphigus vulgaire, pemphigus vegetant et pemphigus paranéoplasique) sont décrites. Chez lesanimaux domestiques, des formes de pemphigus ont été rapportées depuis le milieu des années 70 et la classificationanimale ressemble à celle utilisée chez l’homme. Cet article décrit les données récentes sur l’épidémiologie, les signescliniques, l’histopathologie, l’immunopathologie et le traitement des pemphigus superficiels chez les animaux domes-tiques. Des données détaillées sur le pemphigus foliacé canin, félin, équin et caprin, sur le pemphigus érythémateux caninet félin et sur le pemphigus panépidermique pustuleux canin sont présentées.Resumen En humanos la denominación pénfigo engloba un grupo de enfermedades vesiculares de la piel con sepa-ración intraepidermal resultando en desunión intercelular y acantolisis. Las entidades se clasifican en base al nivel de for-mación de vesículas en la epidermis, y tanto variantes superficiales (pénfigo foliáceo, pénfigo con deposición de IgA) comoprofundas (pénfigo vulgar, pénfigo vegetativo y pénfigo paraneoplástico) son reconocidas. En animales domésticos,variantes de pénfigo han sido reconocidas desde la mitad de la década de 1970, y la clasificación de las enfermedades seasemeja a la utilizada en seres humanos. Este artículo revisa el conocimiento actual sobre la epidemiología, signos clínicos,304 © 2006 The Author. Journal compilation © 2006 European Society of Veterinary Dermatology.
  15. 15. Superficial pemphigus in domestic animalshistopatología, inmunopatología y resultados del tratamiento de las variantes de pénfigo superficial en animales domésticos.Se ofrece asímismo una información detallada sobre pénfigo foliáceo en perros, gatos, caballos y cabras, pénfigo eritematosoen perros y gatos, y pénfigo pustuloso panepidermal en perros.Zusammenfassung Beim Menschen umfasst die Pemphigus-Bezeichnung eine Gruppe von autoimmunen blasen-bildenden Hauterkrankungen mit intraepidermaler Separation, welche aus einer Zell-Zell Loslösung durch Akantholyseresultiert. Die Gruppen werden nach dem Ausmaß der Blasenbildung in der Epidermis eingeteilt, wobei sowohl oberflächliche(Pemphigus foliaceus, IgA Pemphigus) als auch tiefe (Pemphigus vulgaris, Pemphigus vegetans und paraneoplastischerPemphigus) Varianten anerkannt sind. Bei Haustieren sind Untergruppen von Pemphigus seit der Mitte der 1970er Jahrebekannt, und die Klassifizierung der Erkrankung ist jener ähnlich, die für humane Patienten verwendet wird. Dieser Artikelüberarbeitet das neueste Wissen in bezug auf Epidemiologie, klinische Symptome, Histopathologie, Immunpathologie undBehandlungserfolge von oberflächlichem Pemphigus bei Haustieren. Detaillierte Informationen über Pemphigus foliaceusbeim Hund, bei der Katze, beim Pferd und bei der Ziege, über Pemphigus erythematosus beim Hund und bei der Katze,sowie über den panepidermalen pustulösen Pemphigus beim Hund werden geliefert.© 2006 The Author. Journal compilation © 2006 European Society of Veterinary Dermatology. 305