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Abstract Clinical, immunological and histopathological findings in 20 adult dogs of varying breeds with chronic
( 6 months) inflammation confined to the pedal skin were compared over a 2-year period with those of a group
of age-matched controls (n = 20). All affected dogs were pruritic but systemically well. Lesions were present on
all four feet in 18/20 cases. Affected feet were characteristically erythematous, swollen, painful and alopecic. Sinus
tracts were evident in 4/20 dogs. Despite a methodical series of diagnostic tests, no underlying cause was identified.
None of the dogs responded to antimicrobial therapy administered for 8 weeks, none had evidence of
ectoparasitism and none satisfied the criteria for atopic dermatitis. There was no response to a dietary trial using
a novel protein source. The condition was characterized histopathologically by epidermal hyperplasia, hyperkeratosis, spongiosis, dermal oedema and perivascular aggregates of lymphocytes and plasma cells. Clinical signs
did not correlate with histopathological findings. Affected dogs had significantly elevated serum IgG and IgM
concentrations. The results of lymphocyte proliferation assays and phenotypic studies to determine the relative
percentage of CD3+, CD4+, CD8+ and CD21+ lymphocyte subsets, and the ratio of CD4+/CD8+ cells were not
significantly different between groups. No age, sex or seasonal predilections were noted. All dogs subsequently
responded to immunosuppressive doses of prednisolone or cyclosporin. The term immunomodulatory-responsive
lymphocyticplasmacytic pododermatitis is proposed to denote what may be a previously unrecognized condition
in some dogs with pododermatitis of undetermined aetiology.
I NTRO D U CT I ON
Pododermatitis is a common and potentially debilitating disease of dogs.1 Although pedal involvement is a
component of many canine skin diseases, some animals present with lesions confined solely to the foot.2
The clinical history in such cases is often characterized
by periods of disease exacerbation and remission.
Common causes of pododermatitis in the dog include,
but are not limited to, trauma,3 microbial disease,4
ectoparasitism,5 foreign-body reactions6 and immunological skin diseases.1 However, once excluded, there
exists a subpopulation of dogs with disease of undetermined aetiology.4 Although poorly defined, animals
with idiopathic forms of pododermatitis generally have
guarded to poor prognoses.4 Although various predisposing factors have been implicated,68 particular
attention has focused on the potential role of bacterial
infection4,9 and immunological dysfunction.7,9 Consequently, prolonged use of antibacterial therapy has
been advocated to control clinical signs in many
affected individuals.4 Although the rationale for such
Correspondence: Rory Breathnach, Department of Small Animal
Clinical Studies, Faculty of Veterinary Medicine, University College
Dublin, Belfield, Dublin 4, Ireland. Tel.: 0035317166000; Fax:
0035317166022; E-mail: rory.breathnach@ucd.i.e.
364
M AT E R IA L S A N D M E T H O D S
Case selection criteria
The dogs (n = 20; 10 male and 10 female; mean age =
5.4 years) studied were presented to the University
Veterinary Hospital (UVH) of University College Dublin
(UCD) for investigation of pedal skin disease over
the time period 20032004 (Table 1). Animals were
deemed eligible for enrolment once they satisfied a
series of inclusion criteria. Primary criteria included
2005 European Society of Veterinary Dermatology
Case
no.
Breed
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Boxer
Cocker Spaniel
Labrador
Bulldog
Bernese Mountain Dog
West Highland White Terrier
Springer Spaniel
Terrier cross
Labrador cross
Rottweiler
Boxer
Bull Mastiff
Springer Spaniel
Spaniel cross
Labrador cross
Bull Terrier
Pomeranian
Fox-Hound
American Bulldog
Terrier cross
365
Sex
Weight
(kg)
Age
(years)
Duration of pedal
lesions at presentation
(months)
Female
Male
Male
Female
Female
Male
Female
Female
Male
Female
Female
Male
Male
Male
Female
Female
Male
Male
Male
Female
22.1
12.8
31
15.9
47.8
9.2
17.4
11.0
36.2
38.7
22.6
51.4
14.8
17.2
23.8
15.1
3.0
27.6
18.8
11.3
5
6
3
5
2
7
12
2
8
6
5
2
10
2
10
5
6
4
4
4
8
12
7
14
8
16
22
7
12
11
15
6
20
8
18
15
20
6
10
12
Clinical findings
A detailed history was obtained and clinical examination (systemic and cutaneous) performed in each case.
The clinical findings were entered into a database
(Microsoft Excel) to allow subsequent investigation of
any correlation between clinical signs and histopathological findings. Follow-up clinical examinations were
performed at monthly intervals for the first three
months and at three monthly intervals thereafter.
Clinical pathology
Blood samples were obtained by venipuncture for haematology, biochemistry, T4/TSH (thyroid-stimulating
hormone) and immunoglobulin assays. Serum total T4
and TSH concentrations were assayed by chemiluminescence (Immulite, EURO/DPC Ltd, Caernarfon,
Gwynedd, UK). Serum for immunoglobulin assays was
stored at 80 C prior to testing (see succeeding discussions). Urinalysis was performed on free catch samples.
Material for cytological examination was collected
from lesional sites by skin scraping and fine needle
aspiration, and stained with modified Wrights stain
(Diff-Quik, Biosciences, Dublin, Ireland).
366
R M Breathnach et al.
XL-MCL flow cytometer (Beckman Coulter, Buckinghamshire, UK) and associated System II software. A
total of 10 000 cells were enumerated in each run. Lymphocytes were selected based on forward and 90 light
scatter.
Histopathological examination
Biopsies of lesional and control skin were obtained
by scalpel blade excision from the dorsal digital and
palmoplantar surfaces of two feet per dog, placed on
card and fixed in 10% neutral buffered formalin. Morphologic features were evaluated on 6 m, haematoxylin
and eosin (H&E)-stained sections of paraffin-embedded
tissue. Biopsies were sectioned longitudinally to ensure
a consistent plane of orientation.
Statistical analysis
All data were analysed using the statistical package
SPSS version 11 for Windows (SPSS Inc., Chicago,
IL,USA). Correlations between clinical signs and histopathological findings were calculated using Spearmans
test. The haematological/biochemical results were
compared using the independent-samples t-test. For all
remaining data sets, the nonparametric MannWhitney
U-test was employed as the actual and logarithmically
transformed data were not normally distributed. For
all analysis performed, significance was defined as
P < 0.05. Whenever possible, the data were reported as
the median (95% confidence interval).
R E SU LT S
Clinical findings
Males and females were equally represented in this
case series. The mean age for onset of clinical signs was
4.3 years (range: 1.310.2 years), and signs were present
for 622 months (mean: 12.4 months) prior to sampling. All four feet were affected in 18/20 cases examined. Lesions were present on both the dorsal and the
palmoplantar skin surfaces in all cases. Although the
region bordering the pads was affected in 15/20 cases,
lesions involving the pad surface were not observed.
Although not tested statistically, follow-up studies
(data not shown) over a 520-month period revealed
no evidence of a seasonal component to the disorder
or any consistent temporal association with specific
therapeutic agents (anthelminthics, antiparasiticides
or vaccines).
The clinical findings for each dog are summarized in
Table 2. However, it must be emphasized that the data
in Table 2 represent one point in time (day of sampling), and that the clinical signs in each case fluctuated
in line with the dynamic nature of this chronic inflammatory disorder. In 15/20 cases, the lesions started on
one or two feet; thereafter, the lesions increased in
severity and spread to involve the other feet over a
gradual period of 16 months. In the remaining five
dogs, the onset was more acute with all four feet exhibiting clinical signs within a period of 1 month. Over the
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367
Figure 1. Left front foot, case no. 15. Erythema, serous exudation
(SE) and epidermal erosion (Er) of the dorsal interdigital skin in a
10-year old Labrador-cross bitch with lymphocyticplasmacytic
pododermatitis.
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Pruritus
Erythema
Alopecia
Skin thickening
Swelling of toes
Hyperpigmentation
Seropurulent discharge
Serosanguinous discharge
Sinus tracts
Erosions/ulcers
Scarring /web-like appearance
Pain/discomfort
Regional lymphadenopathy
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0
13
5
4
3
2
1
Clinical sign
Case #
10
11
12
14
15
16
17
18
19
20
Figure 2. Right front foot, case no. 19. Erythema, alopecia and
nodule formation on the palmar surface of a 4-year-old male
Bulldog with lymphocyticplasmacytic pododermatitis.
368
R M Breathnach et al.
Serum immunoglobulins
Dogs with pododermatitis (Fig. 3) had a significant
increase in the median serum concentration of both
IgG and IgM (P < 0.05; MannWhitney test).
Proliferation assays
The median (95% confidence interval (CI)) stimulation
index for PBMCs from dogs with pododermatitis was
22.4 (9.547.0), 6.4 (2.215.4) and 11.4 (4.233.8) for
pokeweed mitogen, phorbol myristate and S. aureus
enterotoxin B, respectively; the corresponding values
in the control group were 34.5 (17.482.8), 4.5 (2.2
10.8) and 36.6 (12.588.1), respectively. None of these
differences between groups were significant (P > 0.05;
MannWhitney test).
Histopathology
Figure 3. Serum concentrations (mg L1) of IgA (a), IgG (b) and
IgM (c) in control dogs and dogs with pododermatitis. IgG and IgM
concentrations in the pododermatitis population were significantly
higher (P < 0.05; MannWhitney test). The bar represents the
median value.
Clinical pathology
There was a mild neutrophilia (without left shift) in
4/20 dogs with pododermatitis. Serum alkaline phosphatase values were moderately elevated (< 460 IU L1;
reference range 050 IU L1) in six patients. Significant
increases were recorded in the mean plasma concentrations of potassium and cholesterol in the pododermatitis group (P < 0.05; independent-samples t-test). All
dogs with pododermatitis had serum total T4 and TSH
values within the reference ranges. Four dogs in the
pododermatitis group had 1+ proteinuria. Cytological
examination revealed degenerate neutrophils and
intracellular bacteria at focal pedal sites in one dog
(case no. 3). Although Malassezia organisms were
observed in skin scrapings from five dogs, in each
instance the organism count was < 1 yeast per high
power field (400). Low to moderate numbers of lymphocytes and plasma cells were observed in fine needle
aspirates (FNAs) from 7/20 dogs. Deep skin scrapings
were negative for Demodex spp. mites in all cases.
369
D IS C U S S IO N
370
R M Breathnach et al.
The significant increase in serum IgG concentrations in the affected population was in agreement with
previous findings in dogs with 18 and deep pyoderma,19 although it is noteworthy that a significant
decrease in IgG levels was reported in one study of
dogs with idiopathic deep pyoderma.12 Serum IgM
concentrations were also significantly elevated in dogs
with pododermatitis. The low serum IgA concentrations documented in dogs with antibiotic-responsive
dermatitis20 and pedal pyoderma21 were not a feature
of this case series. Although these results suggest an
up-regulated humoral immune response in dogs with
pododermatitis, a causal relationship between the two
cannot be inferred. Blastogenic responses and relative
percentage values for the different lymphocyte subsets
were not significantly different between groups. In
addition, there was no alteration in the CD4+/CD8+
lymphocyte ratio as reported in demodicosis,22 German Shepherd pyoderma23 or AD (with Malassezia
pachydermatis infection),24 and none of the dogs had
laboratory findings consistent with hypothyroidism.
Although the above assays represent relatively crude methods for assessing cell-mediated and humoral immune
function,25 the results generated here do not suggest a
global B- or T-cell defect in the dogs examined.
The tissue reaction pattern observed on histopathology
provided further insight into the possible presence of
an underlying, nonantibiotic responsive skin disease.
However, a perivascular dermatitis pattern often
represents a stereotypical response to any inflammatory stimulus,26 and does not in itself constitute a specific diagnostic entity.9 Further classification must rely
on other component features within the section, including the predominant cell types involved, the plexus of
blood vessels participating and the nature or extent of
any ancillary morphological changes.27,28 As the predominant cell populations present were lymphocytes
and plasma cells, the term lymphocyticplasmacytic
pododermatitis (LPP) is proposed to reflect the histological appearance of the lesion in keeping with the
long-established approach for alimentary tract and respiratory tract lesions such as lymphocyticplasmacytic
enteritis29 and lymphocyticplasmacytic rhinitis.30 The
presence of other cell types should not detract from the
term proposed, as biopsies from dogs with lymphocytic
plasmacytic enteritis frequently contain additional
neutrophils, eosinophils and macrophages.31 Unfortunately, the data relating to plexus participation and the
ancillary morphological changes within the epidermis
were nonspecific and common to a large number of
skin diseases in the dog.28,32
The presence of large numbers of lymphocytes and
plasma cells within a lesion usually indicates immune
reactivity33 and strongly implies antigenic drive.27
However, mixed lymphoplasmacytic infiltrates have
been reported in both antibiotic-responsive and
immunomodulatory-responsive dermatoses in the dog,
particularly those involving mucocutaneous junctions.34
In this study, all 20 dogs exhibited marked clinical
improvement and longer-term control in response to
AC K N OW L E D G E M E N T S
The authors are grateful to Dr Adrian Dunne and Dr
Michelle Finlay for help with the statistical analysis,
and to the nursing staff within the UVH of UCD who
helped with the animal care and management.
REFERENCES
1. White SD. Pododermatitis. Veterinary Dermatology
1989; 1: 118.
2. Ihrke PJ, Stannard AA, Ardans AA et al. Pemphigus
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
371
372
R M Breathnach et al.
Rsum Les donnes cliniques, immunologiques et histopathologiques observes chez 20 chiens prsentant une
inflammation podale chronique ( 6 months) ont t compares avec celles dun groupe de chien contrle
(n = 20). Un prurit a t not chez tous les chiens atteints, sans atteinte de ltat gnral. Des lsions taient notes
sur les 4 pieds dans 18/20 cas. Il sagissait drythme, denflure, de douleur et dalopcie. Des fistules taient notes
pour 4/20 chiens. Aucune cause na t retrouve malgr des examens complmentaires adapts. Aucun chien na
rpondu un traitement antibiotique de 8 semaines, aucun parasite na t retrouvn et aucun des chiens ne
prsentaient de critres en faveur dune dermatite atopique. Un rgime dviction avec une nouvelle source de
protine na pas permis damliorer la dermatose. Lexamen histopathologique a montr une hyperplasie pidermique, une hyperkratose, une spongiose, un oedme dermique et des aggrgats privasculaires de lymphocytes
et des plasmocytes. Les signes cliniques ntaient pas corrls avec les modifications microscopiques. Les chiens
atteints prsentaient une augmentation significative des IgG et IgM sriques. Des tests de prolifration lymphocytaire et une tude phnotypique nont pas montr de diffrence entre les deux groupes pour les pourcentages
de CD3+, CD4+, CD8+ et CD21+, ni dans le rapport CD4+/CD8+. Tous les cbiens ont correctement rpondu
ladministration de doses immunosuppressives de corticoide ou de cyclosporine. Lappellation pododermatite
lympho-plasmocytaire rpondant limmunomodulation est propsoe pour dcrire cette entit.
Resumen Los hallazgos clnicos, inmunolgicos e histopatolgicos en 20 perros adultos de diversas razas afectados con inflamacin cutnea pedal crnica ( 6 meses) se compararon durante dos aos con aquellos de un grupo
de similar edad (n = 20). Todos los perros afectados presentaron prurito local, pero eran normales en el mbito
sistmico. Las lesiones se presentaron en todas las extremidades en 18/20 casos. Los pies afectados presentaron
eritema, hinchazn, dolor y alopecia. Tractos sinusales se observaron en 4/20 perros. A pesar de realizar una
amplia serie de pruebas diagnosticas, no se encontr ninguna etiologa de fondo. Los perros no respondieron a
una dieta con una protena diferente. A nivel histopatolgico los animales presentaron hiperplasia de la epidermis, hiperqueratosis, espongiosis, edema en la dermis e infiltracin perivascular de linfocitos y clulas plasmticas.
Los signos clnicos no guardaron relacin con los hallazgos histopatolgicos. Los perros afectados presentaron
concentraciones elevadas de IgG e IgM en el suero. Los resultados de proliferacin linfocitaria y los estudios
fenotpicos para determinar el porcentaje relativo de las subpoblaciones linfocitarias CD3+, CD4+, CD8+ y
CD21+, as como la relacin CD4+/CD8+ no fueron significativamente diferentes entre los dos grupos. Tampoco
se observ predileccin en funcin del sexo, edad o estacin del ao. Todos los perros respondieron a dosis
inmunosupresoras de prednisolona o ciclosporina. Proponemos el trmino pododermatitis linfoplasmactica con
respuesta a inmunomodulacin para indicar lo que podra ser una nueva condicin no reconocida previamente
en algunos perros con pododermatitis de etiologa desconocida.
Zusammenfassung Klinische, immunologische und histo-pathologische Befunde von 20 adulten Hunden
verschiedener Rassen mit chronischer ( 6 Monate) Entzndung, die auf die Haut der Pfoten begrenzt war,
wurden ber einen Zeitraum von 2 Jahren mit denen einer Gruppe von Kontrolltieren (n = 20) verglichen,
die altersmig bereinstimmten. Alle betroffenen Hunde zeigten Juckreiz, waren aber ansonsten klinisch
unauffllig. Lsionen waren in 18/20 Fllen an allen vier Pfoten vorhanden. Betroffene Pfoten waren typischerweise erythemats, geschwollen, schmerzhaft und haarlos. Fistelkanle waren bei 4/20 Hunden vorhanden. Trotz
einer systematischen Aufarbeitung mit diagnostischen Tests konnte keine zugrunde liegende Ursache identifiziert
werden. Keiner der Hunde zeigte eine Verbesserung durch eine antimikrobielle Therapie, die ber acht Wochen
verabreicht wurde, keiner hatte Anzeichen von Ektoparasiten und keiner entsprach den Kriterien fr atopische
Dermatitis. Eine Verbesserung durch eine Ausschlussdit mit einer neuen Proteinquelle wurde nicht festgestellt.
Histo-pathologisch war der Zustand charakterisiert durch epidermale Hyperplasie, Hyperkeratose, Spongiose,
dermales dem und perivaskulre Aggregate von Lymphozyten und Plasmazellen. Die klinischen Symptome
korrelierten nicht mit den histo-pathologischen Befunden. Die betroffenen Hunde zeigten signifikant erhhte
Serum IgG und IgM Konzentrationen. Die Ergebnisse der Lymphozyten Proliferationsassays und der
phnotypischen Studien zur Bestimmung des relativen Prozentanteils von CD3+, CD4+, CD8+ und CD21+ Lymphozytengruppen sowie des Verhltnisses von CD4+/CD8+ Zellen, zeigten keine signifikanten Unterschiede
zwischen den Gruppen. Keine Alters-, Geschlechts- oder saisonale Prdilektion wurde festgestellt. In der Folge
sprachen alle Hunde auf immunsupprimierende Dosierungen von Prednisolon oder Cyclosporin an. Der
Begriff immunomodulatory-responsive lymphocytic-plasmacytic pododermatitis (auf immunmodulatorische
Therapie reagierende lympho-plasmazellulre Pododermatitis) wird vorgeschlagen, um einen eventuell bisher
nicht erkannten Zustand bei manchen Hunden mit Pododermatitis von unbekannter tiologie zu bezeichnen.