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Veterinary Dermatology 2006, 17, 51 62

Blackwell Publishing Ltd

A retrospective study of cutaneous equine sarcoidosis


and its potential infectious aetiological agents
IAN B. SPIEGEL*, STEPHEN D. WHITE, JANET E. FOLEY, NICOLE L.
DRAZENOVICH, PETER J. IHRKE and VERENA K. AFFOLTER
*Veterinary Medical Teaching Hospital, Department of Medicine and Epidemiology, Center for Vectorborne
Disease, Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University
of California, Davis, California 95616 USA
(Received 1 June 2005; accepted 1 November 2005)

Abstract Nine horses from ages 5 to 21 years were diagnosed with cutaneous equine sarcoidosis (ES) over an
18-year period. In addition to skin, the lungs were frequently involved, with other organ systems affected less
commonly. A predisposition for thoroughbreds and geldings was noted. Cutaneous lesions and signs included
crusts, scales, alopecia and pruritus. These were found at various sites, particularly the legs/thighs/elbows, thorax,
neck, face and ventral abdomen. Three horses were euthanized shortly after hospitalization; others survived as
long as 12 years. Histopathologic stains, immunohistochemistry and polymerase chain reaction assays on paraffinembedded cutaneous specimens from eight horses for Mycobacterium spp., Coccidioides immitis, Cryptococcus
neoformans, Corynebacterium pseudotuberculosis, and Borrelia burgdorferi were all negative. The aetiology of ES
is unlikely microbial and continues to be a diagnosis of exclusion. ES, when limited to the skin, is associated with
a good prognosis, with either partial or complete response to glucocorticoid therapy in all the surviving horses.

IN TRO D U CT I ON
Equine sarcoidosis (ES), also known as equine idiopathic systemic granulomatous disease,1 generalized
granulomatous disease,2 systemic granulomatous disease,3 equine histiocytic disease2 and equine histiocytic
dermatitis,4 is a rare multisystemic noncaseating primarily granulomatous and lymphoplasmacytic disease
of unknown aetiology. It is characterized by skin lesions,
involvement of one or more internal organs and often
severe wasting,2,5,6 and has been reported in horses,
cattle, and humans.1,7,8 In horses, the organs most
commonly affected are the skin, lungs, lymph nodes
and gastrointestinal tract.2,5,9,10 Other organs or tissue
reportedly affected include liver, spleen, kidney, the
skeletal system, heart, adrenal gland, thyroid glands,
pancreas and the nervous system.6
Stannard classified the skin lesions of equine sarcoidosis into two forms: (a) scaling and crusting, and
(b) nodular or tumour-like masses.3 The former is more
common and is associated with the classical presentation
of a focal or multifocal exfoliative dermatitis with
initially local or generalized extensive scaling and crusting, and a variable degree of alopecia as the disease
progresses, especially on the legs and the face, often
sparing the mane and the tail.11 In addition, a third form
has been proposed, that is characterized by hyperkeratotic,
crusted, alopecic plaques, especially on the legs (localized)
in an otherwise systemically healthy horse.6,12 Serum
Correspondence: Ian B. Spiegel, Red Bank Veterinary Hospital,
197 Hance Avenue, Tinton Falls, NJ, 07724 USA. Tel.: +732 747
3636; Fax: +732 747 6562; E-mail: ian.spiegel@rbvh.net

exudation may be associated with these lesions.2 The


onset of skin lesions is often insidious, but may be
rapid.13 Other noncutaneous clinical signs commonly
seen are persistent low-grade fever, exercise intolerance,
mild respiratory distress, weight loss, diminished appetite,
peripheral lymphadenopathy, diarrhoea, icterus and
lameness.5,6,14
Currently, ES is a diagnosis of exclusion. The most
likely differential diagnoses include dermatophytosis,
dermatophilosis, pemphigus foliaceus, erythema
multiforme, drug eruptions, multisystemic eosinophilic
epitheliotrophic disease, equine systemic lupus erythematosus-like syndrome and toxicoses from arsenic, iodine,
aluminium, silicon or hairy vetch.3,6 Clinical management is often problematic. In some horses, the disease
may regress spontaneously, whereas in others it responds
to corticosteroid (e.g. dexamethasone or prednisolone)
treatment.
Although the aetiology of sarcoidosis in humans is
unknown, it is hypothesized to be the result of an exaggerated immunologic response of the helper/inducer
T-cell arm of the immune system to an antigenic stimulus,
such as an exogenous infectious agent or allergen.8,15,16
This cell-mediated immune response is suspected in
horses.5,6 Although controversial, association of sarcoidosis with tuberculosis (Mycobacterium spp.) in humans
has been postulated because of the similar histopathology
seen in both conditions.16 Polymerase chain reaction
(PCR) assays have been utilized by numerous investigators of human sarcoidosis, and have enabled the detection
of multiple species of mycobacterial DNA in sarcoid
granulomas/lesions (e.g. skin and lungs).1721 Fungial
including cryptococcal (Cryptococcus neoformans),

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IB Spiegel et al.

infections have also been associated with human


sarcoidosis,22 and other fungi, such as Coccidioides
immitis, are potential causative agents, as the cutaneous
lesions, systemic signs and histologic changes of the
diseases are similar.6 C. immitis has been reported in
individual human patients, including women treated
with corticosteroids for sarcoidosis.23
Although reference to cutaneous ES is common
in the literature of equine skin diseases,26,14 peerreviewed reports are rare. Available data suggest that
the syndrome is the result of persistent antigenic drive
or immunologic response to an unknown trigger.5 In
addition to suspected infectious aetiologies, other
causes have been proposed, such as toxicosis with Vicia
villosa (hairy vetch), and other related plant species.24,25
Hairy vetch toxicosis has been more commonly reported
in cattle in certain regions of the United States 26,27 and
other areas of the world, including South America.28
However, as ES is also observed in geographic regions
and pastures where hairy vetch is absent, hairy vetch
toxicosis is unlikely to be a common cause of ES.
Mycobacteria spp., C. immitis, C. neoformans,
Corynebacterium pseudotuberculosis and Borrelia burgdorferi, chosen for a variety of reasons, were investigated
as possible aetiologies for ES. In addition to controversial
association with human sarcoidosis, Mycobacterium
spp. have rarely been implicated as the cause of cutaneous
lesions in horses similar to those reported with ES.29
C. immitis is commonly present in geographical areas
with low rainfall and high temperature such as in northern
California where this study took place.30 C. neoformans
was included because it has been reported in human
sarcoidosis.31,32 It has been suggested that both C. immitis
and C. neoformans may cause secondary infections
in human sarcoidosis because of immune suppressive
conditions associated with either the disease or immunosuppressive treatment.23,33 C. pseudotuberculosis is
a well-recognized pathogen in horses.34 Because some
species of Corynebacterium produce clinical syndromes
in humans such as granulomatous lymphadenitis, pneumonitis, pharyngitis, cutaneous infections and endocarditis35 (thus potentially mimicking the granulomatous
reaction of sarcoidosis), they have been implicated in
the pathogenesis of human sarcoidosis.36
B. burgdorferi was included because of the presence
of Borrelia DNA in one horse out of three with ES with
positive titres to the spirochete.37 However, although 30
of 55 (54.6%) human sarcoidosis patients had antibodies
to B. burgdorferi, no organism DNA was found in the
granulomatous tissues.38
In horses, there has been minimal success in investigating possible aetiological agents of ES using cultures
(for fungi, aerobic, anaerobic and acid-fast bacteria),
special histologic stains (acid-fast, periodic acid-Schiff,
Gomoris methenamine silver, auramine O), electron
microscopy, animal inoculation studies, direct immunofluorescence and immunoperoxidase testing.5,10,39
The objective of this retrospective study was to
identify potential infectious agents that might be
responsible for ES in horses using special histological

stains, immunohistochemistry and PCR from paraffinembedded biopsy samples of the skin and other available
tissues. In addition, this study reports and summarizes
the signalment, initial presenting clinical signs and
histopathologic changes seen with equine ES, the effectiveness of treatment modalities used and the clinical
outcome.

M AT E R IA L S A N D M E T H O D S
Case material
The data from 15 horses diagnosed with ES at the
Veterinary Medicine Teaching Hospital of the University of California at Davis (UCD-VMTH) and IDEXX
Laboratories Incorporated in West Sacramento, California
were retrieved using a computer-based search for equine
biopsy samples between 1981 and 2004. The diagnosis
of systemic granulomatous disease included the terms
equine sarcoidosis, chronic granulomatous disease,
idiopathic systemic granulomatous disease, sterile granulomatous disease and/or hairy vetch poisoning. ES
was established primarily on histopathologic examination of affected organs but also on history, laboratory
results, clinical signs and elimination of other causes of
granulomatous disease. Cases included were chosen on
the basis of history and physical examination, histological
confirmation of lesions consistent with ES and availability of medical records and paraffin-embedded tissue
samples.

Clinical data
Clinical data for horses with cutaneous ES were collected
from the medical records, and additional information
was obtained from telephone interviews with the referring
veterinarians and /or owners. The data included signalment
(age, breed, gender), age of onset, age at diagnosis, prior
history of skin disease, presenting complaints, clinical
signs at presentation, onset of clinical signs, disease
progression, results of clinical pathology, imaging,
histopathologic examination, treatment and outcome.

Histopathology and immunohistochemistry


Two of the authors (IBS and VKA) evaluated archived
haematoxylin and eosin (H&E) sections of formalin-fixed
paraffin-embedded tissues (skin and other organs, such
as lung and lymph nodes if available) from all 15 cases.
These were reviewed for the presence of: multifocal
nodular to diffuse noncaseating granulomatous dermatitis with histiocytes, multinucleated giant cells and
fewer lymphocytes and specimens from nine horses
met all inclusion criteria (Table 1). The paraffin blocks
were no longer available for horse 2, but the special
stains performed at the time of biopsy submission were
reviewed. In the remaining eight cases, special stains
including Gomoris methenamine silver (GMS);
Fites modified acid-fast (Fite-Faraco); and Brown and
Brenn (B&B) were repeated and evaluated. Positive
control tissue was included for each special stain
and processed simultaneously. Immunostaining with

2006 The Authors. Journal compilation 2006 European Society of Veterinary Dermatology

Equine Sarcoidosis
Table 1. Signalment (age of onset, breed,
gender), duration clinical signs prior to
diagnosis, and organs involved

53

Horse
number

Age at time
of diagnosis
( years)

Breed* Sex

Duration of
clinical signs prior
to diagnosis
(estimated in months)

1
2
3
4
5
6
7

17
10
21
13
10
5
13

TB
QH
AAX
TB
TW
TB
TB

G
M
G
G
G
G
G

3
1
1
2
2
6
1

8
9

20
30

QH
TB

S
G

Unknown
23

Organs involved
S, LG, LV, LN, GI, K
S, LG, LN, MG, BM
S
S
S, LG, B (cervical vertebrae)
S, LG
S, LG, GI, B
(lateral femoral condyle)
S
S

*TB, thoroughbreds; QH quarter horses; AAX, Arabian-Appaloosa cross; TW, Tennessee


walker.
G, gelding; S, stallion; M, mare.
S, skin; LG, lung; LV, liver; LN, lymph node; GI, gastrointestinal tract; K, kidney; BM, bone
marrow; B, bone (suspected involvement); MG, mammary gland.

anti-Bacille Calmette-Guerin (BCG) antibodies was


used for the identification of microorganisms.40

PCR assays and DNA sequencing


DNA was extracted from a total of 57 tissue samples
(including skin samples for horses 1 and 39, and nonskin tissue samples from horses 1 and 57) and tested
by PCR.41 Two 50 m sections from paraffin-embedded
formalin-fixed cutaneous tissue samples and other
available lesional tissues (lung, lymph node and
gastrointestinal tract), were placed in 1.5-mL tubes,
deparaffinized with xylene (Merck, Rahway, NJ) and
washed with ethanol. They were then suspended in
Buffer ATL (liquid-proprietary compound mixture
containing edetic acid and sodium dodecyl sulphate)
and proteinase K from a kit (Qiagen DNeasy tissue
kit, Valencia, CA), mixed with 100 L of 0.1 mm glass
beads (Cole Parmer, Vernon Hills, Illinois), mixed at
a high vortex setting for 5 min (Disrupter Genie, USA
Scientific, Ocala, FL), and incubated overnight at
55 C. The tissue was then extracted with a commercial
kit (Qiagen, Valencia, CA).
Controls. In all PCR methods, a nested PCR with a
target sequence within the glyceraldehyde-3-phosphate
dehydrogenase (GAPDH) gene was used to prove
the presence of amplifiable DNA. Results of all PCR
assays were considered positive if the threshold cycle
(Ct) value was equal to 40.
For Mycobacterium spp., amplification of the 16S
rRNA gene region was performed as previously
described,42 using primers 246 (5-AGAGTTTGATCCTGGCTCAG) and 247R (5-TTTCACGAACAACGCGACAA) for the first round, and M1 (5-AGTGGCGAACGGGTGAGTAAC) and R7 (5-TTACGCCCAGTAATTCCGGACAA) for the second round, in a
thermal cycler (MJ Research, Watertown, MA). DNA
extraction and PCR were performed in separate rooms
with separate equipment including plugged injector
tips. The products were separated by electrophoresis
through 1% agarose gel and visualized with ethidium

bromide. All PCRs were run with a positive and negative control. Similar protocols were used with the other
infectious agents. For C. pseudotuberculosis, the phospholipase D (PLD) toxin gene was used. Amplification
was performed with an ABI 7700 Prism Sequence
Detector (Applied Biosystems, Foster City, CA) and
the products were analysed with the accompanying
software.43 Each 12-L reagent contained 1X Taqman
Universal Master Mix (Applied Biosystems), 2 nmol
each primer, 400 pmol probe, and 1 L DNA. The
thermocycling conditions consisted of 50 C for 2 min,
95 C for 10 min, and 40 cycles at 95 C for 15 s, followed
by 60 C for 1 min. For B. burgdorferi, a TaqMan assay
was used44 and for the subtyping of C. neoformans,
DNA extraction and PCR restriction fragment length
polymorphism analysis of the phospholipase B (PLB1)
gene was performed.45 The DNA extraction and PCR
protocols followed for C. immitis were those described
by Greene and colleagues.46

Statistical analysis
Data were maintained in Excel 2002 (Microsoft,
Redmond, WA) and analysed in R (The R-Development
Core Team, www.r-project.org). Summary statistics were
compiled for signalment, clinical findings and onset/time
of diagnosis. Values of P < 0.05 were considered significant. Association of equine breed, age and gender
with ES was analysed with the chi-squared or Fishers
exact test. Results and common trends in laboratory values
were reported for horses affected with cutaneous ES.

R E SU LT S
Tissue sample analysis
Of the 15 horses initially evaluated, clinical data were
collected from only nine that exhibited histologic
changes typical for ES (Table 1). The diagnostic skin
samples were obtained in winter (5/9), spring (1/9),
summer (1/9) and autumn (2/9). Onset of clinical signs
was reported in eight of the horses.

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Table 2. Clinical signs


Horse
number

Alopecia
crusting*
scaling

Pain or
pruritus
location

Anatomical
skin lesions

Systemic
lymph signs
reported

A, C, S

Pr

MRF, L, E, N, T (thighs)

Pn

T (localized)

3
4
5

Not reported
Not reported
Pr, Pn

L, VA
MRF, L, BK, T (thigh)
MRF, L, BK, N, VA

A, C, S
C
A, C, S
(scarring alopecia)
A, C

Pr, Pn

A, S

Pr

8
9

C, S
C

no Pr
Pr

MRF, VA, T, N, BK, E


(not pectoral)
L (elbow, inguinal), VA
(caudal area/sheath)
diarrhoea depression
N (and other not reported)
L, T, N

Anorexia weight loss


depression
Mild anorexia fever
depression
Weight loss
Weight loss
Not reported
Weight loss

Enlarged nodes
or oedema
Oedema
(submandibular)
Not reported
Oedema (leg)
Lymphadenopathy
Lymphadenopathy
oedema (leg)
Lymphadenopathy

Anorexia
Weight loss

Lymphadenopathy

Unknown
None

Unknown
Not reported

*A, alopecia; C, crusting; S, scaling (based on available information).


Pn, pain; Pr, pruritus (based on available information).
MRF, mandibular region/face; L, legs (including thighs and elbows); VA, ventral abdomen; T, thorax; N, neck; BK, back; E, ears
(all had diffuse cutaneous lesions except for horse # 2).

Figure 1. Areas of alopecia, with some scaling and crusting of a


horse with chronic granulomatous disease. (C, crusts; S, scales).

Cutaneous lesions and signs. Skin lesion distribution


and the affected regions are listed in Table 2. These
were generalized except for horse 2, that had lesions
localized to the dorsal thorax. Crusts were present in
eight of the horses, and scales and alopecia/partial
alopecia in five. Pruritus was reported to be present in
five horses. There was associated pain in two pruritic
horses and in one nonpruritic horse. For horse 9, the
clinical record was incomplete. Figures 14 show the
alopecia and typical crusts and scales of ES lesions. In
horse 6, generalized cutaneous ES was reported, but
the legs and pectoral areas remained unaffected. The
duration interval from initial clinical signs to diagnosis
ranged from approximately 16 months with a median
of 2 months and mean of 2.3 months. Three of the
horses had a record of previous skin disease distinct
from their presenting complaint: an undiagnosed
cutaneous nodule in the saddle region, a histologically
confirmed nongranulomatous exfoliative dermatosis
and a subcutaneous C. pseudotuberculosis abscess present
4 years previously.

Clinical data
Signalment. Details regarding the signalment (age,
breed and gender) are listed in Table 1. A significant gender predilection was observed (P = 0.019).
The mean age was 13.6 years and median age was
13 years.
General clinical findings. All nine horses presented
with skin lesions; five had other organs affected
(Table 1). Radiographs suggested the presence of bone
lesions with periosteal reaction and possible bone
marrow involvement of the lateral femoral condyle in
horse 7 and an osteopenic lesion in the cervical vertebrae in horse 4, but these were not confirmed by histologic
examination. The five horses with pulmonary lesions
(1, 2, and 57) had diffuse interstitial pulmonary
opacity/density on radiographs.

Systemic clinical signs. Other clinical signs, recorded


in Table 2, included weight loss, lymphadenopathy,
peripheral oedema, depression and diarrhoea. Two
horses reportedly had an excellent appetite in the face
of weight loss; anorexia was reported in only three.
An elevated rectal temperature was noted in one
(40.4 C; horse 2).
Laboratory information. Laboratory information (Table 3)
including complete blood cell count (CBC) and biochemical profiles were available for seven of the nine
horses.
Erythrocyte morphology abnormalities reported
included anisocytosis and rouleaux formation in six
and five horses, respectively. The creatinine kinase (CK)
was mildly elevated in four horses. The electrolyte

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Figure 4. Areas of partial alopecia along the dorsum with


a moderate degree of crusting and scaling.

and 1:320 (positive)) and coccidioidomycosis serology/


titre (two negative immunodiffusion and complement
fixation tests). No dermatophytes were cultured from
the four horses tested.
Treatment. The treatment received by each of the nine
horses is shown in Table 4. Exact doses for medications
were unavailable in some cases as body weights were
not always recorded. Frequency of use and techniques
used for topical treatments were unclear. Table 5 lists
recorded dosages.

Figure 2. Prominent alopecia with some scaling of the face and ears.
(A, alopecia; C, crusts; S, scales).

Figure 3. Higher magnification of the alopecia and extensive scaling


of the neck. (A, alopecia; S, scales).

(potassium, sodium and chloride) profiles of the horses


were unremarkable. Other tests infrequently performed
and reported included: antinuclear antibody test (1 negative), equine infectious anaemia Coggins (1 negative),
C. pseudotuberculosis titre (two horses; 1:8 (negative)

Clinical follow-up/outcome. Horses 1 and 2 were euthanized less than 1 month after presentation as both
had multiple organ involvement and did not respond to
treatment. Horse 7 had several organ systems involved,
including the femoral bone, was unresponsive to oral
prednisolone, and was euthanized 3 months after discharge from the hospital.
The remaining six horses survived, and the relevant
case-specific information is outlined in Table 3. Horses
3, 4, 8 and 9 had only skin involvement. Horse 6 was
the only horse with lung disease in which all lesions
completely resolved.
There was either partial or complete response in all
of the horses treated with glucocorticoids that survived
the past 3 months. Information regarding exact course
or use of glucocorticoids was difficult to assess, as followup information was not always available. No horse with
skin lesions only was euthanized. Follow-up was available for four of the horses (horses 3, 5, 8 and 9) alive
longer than 3 months after the diagnosis. The disease
in horse 5 regressed after a 6-month tapered course of
oral prednisolone and the horse was still alive for over
8 years with alopecic scarring in previous lesional areas
and orthopaedic age-related changes. The disease in
horse 8 spontaneously regressed, recurred in the same
season (autumn) the following year, and then regressed
again. Horse 9 responded to oral corticosteroids and
antibiotics and subsequently moved and was lost to

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Table 3. Blood screen findings


Horse
number
1

3
4
5

6
7

Clinical chemistry*

Haematology

AST (796 IU L ; normal 138 409 IU L )


T-bili (42.3 mol L1; normal 8.5 39.3 mol L1)
BUN (12.9 mmol L1; normal 4.3 9.6 mmol L1)
GGT (65 IU L1; normal 8 22 IU L1)
SD (12 IU L1; normal 0 8 IU L1)
globulin (52 g L1; normal 17 47 g L1)
T-bili (42.3 mol L1; normal 8.5 39.3 mol L1)

neutrophils (9425 neutrophils L1; normal 2600 6800 neutrophils L1)


fibrinogen (7 g L1; normal < 4 g L1)

neutrophils (10 948 neutrophils L1; normal 2600 6800 neutrophils L1)
monocytes (1292 monocytes L1; normal 0 500 monocytes L1)
fibrinogen (6 g L1; normal < 4 g L1)
lymphocytes (1156 lymphocytes L1; normal 16005800 lymphocytes L1)
haematocrit (27%; normal 30 46%)
lymphocytes (1200 lymphocytes L1; normal 1600 5800 lymphocytes L1)
T-bili (44.5 mol L1; normal 8.5 39.3 mol L1) leucocytes (10 400 leucocytes L1; normal 5000 11 600 leucocytes L1)
lymphocytes (1352 lymphocytes L1; normal 1600 5800 lymphocytes L1)
globulin (55 g L1; normal 17 47 g L1)
neutrophils (13 376 neutrophils L1; normal 2600 6800 neutrophils L1)
GGT (23 IU L1; normal 8 22 IU L1)
leucocytes (15 200 leucocytes L1; normal 5000 11 600 leucocytes L1)
fibrinogen (5 g L1; normal < 4 g L1)
1
1
GGT (14 IU L ; normal 8 22 IU L )
globulin (68 g L1; normal 17 47 g L1)
neutrophils (10 744 neutrophils L1; normal 26006800 neutrophils L1)
fibrinogen (5 g L1; normal < 4 g L1)
haematocrit (29.9%; normal 30 46%)

Note: horses 8 and 9 did not have laboratory work available/performed. Key: = increased/above normal and = decreased / below normal
*AST, aspartate aminotransferase; T-bili, total bilirubin; BUN, bloodurea nitrogen; GGT, gamma-glutamyl transpeptidase; SD, sorbitol
dehydrogenase.

Table 4. Treatments used, outcomes, and other case-specific information


Horse
number

Oral
steroids*

Injectable
steroids*

NSAID

Other treatments

No

DEX (IV)

No

2
3

No
DEX

No
No

PBZ
No

TMS selenium sulphide


(topical)
TMS
Testosterone (oral)
Captan (topical)
Copper naphthenate
(topical)
Not reported
Not reported

4
5

PRED
PRED

No
DEX (IM)

No
PBZ

PRED

No

No

7
8
9

PRED
No
DEX

No
No
No

No
No
No

Mineral oil (topical)


Glycerine (topical)
Selenium sulphide
(topical)
Not reported
No
Hydroxyzine (oral)
TMS (oral)
Povidone-iodine
(topical)

Known outcome and casespecific information (survival)


and other comments
Euthanized < 2 months
after diagnosis
Euthanized < 2 months after diagnosis
Alive 12 years after diagnosis,
dead when
Manuscript published

Alive at discharge; lost to follow-up


Alive > 8 years after diagnosis, alive when
Manuscript published
Alive at discharge (3 months improved),
Lost to follow-up

Alive at discharge, euthanized 3 months later


Alive when manuscript published; seasonal
Alive when manuscript published

*DEX, dexamethasone; PRED, prednisolone.


NSAID, nonsteroidal anti-inflammatory drug.
PBZ, phenylbutazone.
TMS, sulfamethoxazole and trimethoprim.

follow-up. Horse 3 resolved after receiving dexamethasone for 2 weeks with minimal improvement and
2 months of testosterone supplementation. The latter
had been gelded several months before skin lesion
development and was lesion free for an additional
12 years.

Histopathologic and immunohistochemical


findings
The skin of all nine horses had predominantly nodular
to occasionally diffuse granulomatous dermatitis characterized by irregular foci of histiocytes (with variably
vacuolated cytoplasm) and multinucleated giant cells

2006 The Authors. Journal compilation 2006 European Society of Veterinary Dermatology

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Table 5. Medication dosages


Horse
number
1
2
3
4

5
6
7
8
9

Dose information* (where available)


Corticosteroids (dexamethasone 20 mg IV b.i.d.) and antibiotics (sulfamethoxazole and trimethoprim, 12 tablets orally b.i.d.;
tablet size unreported).
Phenybutazone (2 g in AM and 1 g in PM orally) and antibiotics (sulfamethoxazole and trimethoprim 15 tablets orally b.i.d.;
tablet size unreported).
Testosterone supplementation orally (dose unavailable) for two months after a 2-week course of dexamethasone (20 mg orally
b.i.d. and taper).
Oral prednisolone (unknown dose), 0.04 mg kg1 of dexamethasone intramuscularly once daily for 5 days, then prednisolone
1.7 mg kg1 orally once a day for 2 weeks, then 1 mg kg1 orally once a day for 2 weeks, and finally tapered to once every other
day.
This horse also received 2 mg kg1 of phenylbutazone orally twice daily as needed for neck stiffness.
Oral prednisolone (1.3 mg kg1 orally b.i.d. for 3 weeks, then 1.3 mg kg1 orally s.i.d. with a taper of 50 mg week1 for at least
2 months.
Oral prednisolone (1.3 mg kg1 orally s.i.d. for 5 weeks then e.o.d.).
No treatment reported.
Dexamethasone orally (0.02 mg kg1 q.i.d. for 3 days, then 0.01 mg kg1 q.i.d. for 3 days, then the same dose e.o.d. for 5 days)
along with a course of hydroxyzine pamoate (0.9 mg/kg orally b.i.d. for 2 weeks) and antibiotics (sulfamethoxazole and
trimethoprim 30 mg kg1 orally b.i.d. for 14 days).

*b.i.d., twice daily; s.i.d., once daily; e.o.d., every other day.

Figure 5. Horse 1: dermal nodule composed of predominantly


epithelioid macrophages (M) and multinucleated giant cells (G).
Connective tissue is prominent (CT). (H&E. Magnification
bar = 100 m).

Figure 6. Horse 7: a predominant marginal infiltration of


lymphocytes (L) is associated with the histiocytic nodule and
giant cells (G). Some blood vessels are also noted (BV).
(H&E. Magnification bar = 50 m).

(Fig. 5). There were fewer lymphocytes and rarely neutrophils. In most instances, the dermal inflammatory
nodules were not associated with follicular or adnexal
structures. In horse 1, although the nodules appeared
more closely associated with hair follicles, there was
no evidence of folliculitis. In horses 3 and 6, increased
neutrophils were associated with the granulomas, which
illustrate the possibility of a slightly different presentation
of the same condition. Horse 7 had an increased number
of lymphocytes throughout the sections, especially
associated with giant cells (Fig. 6). Other common but
nondiagnostic findings included mild acanthosis,
mild diffuse hyperkeratosis, mild spongiosis and layered
crusts composed of parakeratosis, degenerating inflammatory and epithelial cells and serum.
Special stains including GMS, Fite-Faraco, and B&B
and immunohistochemistry for BCG were applied in
eight cases. All the special histological stains were negative, with the exception of B&B stains, which revealed
the presence of large gram-positive narrow bacilli in

granulomatous (inflammatory) and noninflammatory


areas in tissues from six horses (75%) (Figs 7 and 8). These
pathogens were most consistent with Clostridium spp.

PCR analysis
Nested PCR for the target sequence within the housekeeping gene, GAPDH, revealed amplifiable DNA in
100% of the tissues in the eight horses evaluated. However,
PCR analysis for mycobacterial, coccidioidal, cryptococcal, corynebacterial or B. burgdorferi DNA were
negative in all horses, including horse 3 with a positive
serological titre to C. pseudotuberculosis.

D IS C U S S IO N
Cutaneous sarcoidosis in horses presents with skin
lesions different from those reported in the human
disease. Generalized exfoliative lesions may be seen
but the most typical signs are crusting, scaling and

2006 The Authors. Journal compilation 2006 European Society of Veterinary Dermatology

58

IB Spiegel et al.

Figure 7. Horse 8: large gram-positive straight bacilli (B)


in granulomatous (inflamed) areas (B&B. Magnification
bar = 500 m). These are likely the result of contamination
in sampling or processing.

Figure 8. Horse 7: large gram-positive straight bacilli (B)


in noninflamed areas (B&B. Magnification bar = 500 m).
These are likely resulting from contamination in sampling
or processing.

alopecia occurring on the face, girth area, ventral


abdomen, axillary and inguinal region, neck, shoulder,
legs, prepuce and scrotum.1,9,10,13,37 In one case report,
eventual involvement of over 60% of the skin surface of
a miniature pony was described,1 whereas others describe
the typical clinical signs, and occasional nodules.1,9,10,13,37
The majority of lesions in the present study conformed
to the general pattern and were observed on extremities,
including legs, thighs and elbows, neck and thorax, as
well as the ventral abdomen, mandibular region, face,
ears), and back. More than half of the horses studied
were pruritic. Previous retrospective studies and case
reports did not mention this finding,1,9,10,13,37 and it is
possible that pruritus was present and not reported, as
one text states that horses with cutaneous sarcoidosis
are often pruritic.47 Pruritus has been reported as a clinical
sign for human cutaneous sarcoidosis.48
Noncutaneous clinical signs of ES, indicating systemic
involvement, include weight loss, anorexia, respiratory
distress, peripheral lymphadenopathy, fever and exercise
intolerance.1,9,10,37 These are similar to observations in
humans with sarcoidosis.8,49,50 In this study, over half
of the horses had weight loss, possibly the result of anorexia
or, alternatively, granulomatous inflammation of the
gastrointestinal tract with subsequent malabsorption of
nutrients. Gastrointestinal lesions, which have been reported
previously in horses9 and in humans,51 were confirmed
in one horse and suspected in another, with nonremitting
diarrhoea. These two horses were euthanized within 1 and
3 months respectively, suggesting a poor prognosis associated with gastrointestinal tract involvement and ES.
More than half of the horses had lung involvement
with a diffuse interstitial pulmonary opacity/density
depicted on radiographs. Pulmonary lesions are commonly reported in ES1,5,9 and human sarcoidosis.5255
Lymphadenopathy, a common characteristic of
human sarcoidosis50,53,55 and ES,1,9,10 was detected in
three of the horses in this study. Peripheral oedema,
seen in three horses, has previously been reported in ES,10
and is an unusual presentation of human sarcoidosis.56

Additional clinical signs depended on the organ system


involved. Radiographs showed lesions on the lateral
femoral condyle and cervical vertebrae of two horses.
Although not reported previously in horses, vertebral
sarcoidosis occurs in human sarcoidosis57 where the
bone is commonly affected.55 The lesions in liver, kidney
and mammary gland tissues were similar to earlier
findings.9 Liver and kidney involvement occurs in
human sarcoidosis.58,59
Other organs reported to be affected in humans
include spleen,15 the musculoskeletal system,60 cardiac,61,62 neurological system63 and the eyes.64 Ocular
involvement in the horse has not been reported,11 but
involvement of the spleen, heart and neurological
system has been reported in ES,6 including a case of
encephalitis in the absence of concurrent skin involvement.65 Although these were not specifically identified
or investigated in the present study, the range of potential
organ involvement needs consideration in ES.
The neutrophilia, hyperfibrinogenaemia and hyperglobulinaemia found are commonly reported with
ES.1,5,9,11,37 These values are probably increased, at
least in part, because of inflammation. Additional data
reported are mild nonregenerative anaemia, hypercalcaemia and abnormal kidney and liver function
tests.1,5,9,11,37 Elevated globulin levels are to be expected
with prominent inflammatory lesions as seen with
sarcoidosis. None of the nine horses in this study had
hypercalcaemia, but many had neutrophilia, hyperfibrinogenaemia, hyperglobulinaemia, and two horses
had a mild nonregenerative anaemia.
The age range of 521 years is similar to previous
reports of affected horses (3 months to over
20 years),1,9,10,13,37 and suggests no age predilection
for ES. Cutaneous ES may have a predilection for
thoroughbreds. However, as breed distribution was not
compared with that of a reference population, and case
numbers were small, it was not possible to determine
whether or not thoroughbreds were statistically overrepresented. Nevertheless, this observation is similar to

2006 The Authors. Journal compilation 2006 European Society of Veterinary Dermatology

Equine Sarcoidosis
that of previous reports.9,10,37 Given the small numbers,
males and geldings in particular were significantly
over-represented, although a firm conclusion on gender
predilection for ES was not possible. This was also true
of two previous reports of cutaneous ES.13,37 However, in
humans, women are affected two to eight times more
frequently than men.16 As geldings appear over-represented,
it would be interesting to determine if there is a temporal
association between ES and castration. One horse in
this study was healthy for 15 years, and according to
the owner, within 2 months of the castration, developed
lesions that resolved after 2 months of oral testosterone
treatment. The horse then remained lesion free for 12 years.
ES appears to be seasonally independent; only one horse
presented with repetitive transient seasonal clinical
signs and other retrospective studies did not report a
seasonal influence.13,24 However, the season seems to
influence development of sarcoidosis in humans.6669
Previously, the prognosis given for recovery from
ES has been poor.2,6 This study indicates a more favourable
prognosis, particularly if fewer organ systems are involved.
Even horses with involvement of several organ systems
survived for many years. Gastrointestinal involvement
suggests a poor prognosis, whereas ES limited to the
skin suggests a good prognosis.
To the authors knowledge, this is the first attempt to
investigate potential infectious aetiologies of ES using
a combination of multiple histological stains, immunohistochemistry and PCR to detect intralesional DNA
of Mycobacterium spp., C. immitis, C. neoformans,
C. pseudotuberculosis, and B. burgdorferi. PCR is a
highly sensitive and specific technique when run with
appropriate controls but false-negative results may
occur as a result of (a) degraded target DNA, (b) PCRinhibiting substances present in tissue specimens, or
(c) insufficient extraction of target DNA.70 The latter is
particularly a concern for mycobacteria as these bacteria
are difficult to lyse because of the lipid-rich cell wall.71
Degradation of the target DNA is also a concern, as many
of the current samples were greater than 510 years old
and had been fixed in formalin, which can diminish the PCR
amplification signal.72 However, good-quality GAPDH
signals were obtained with all of the samples, indicating
that the horse DNA had been efficiently extracted.
The negative PCR results, immunohistochemistry
and special histological stains were negative for
acid-fast bacteria, all suggesting that ES is unlikely
to be caused by an active mycobacterial infection.
The failure to detect mycobacterial DNA in any of the
paraffin-embedded samples tested accords with the
results of some studies of human sarcoidosis using
PCR.73,74 Other PCR studies of human sarcoidosis
have sometimes detected mycobacterial DNA (especially Mycobacterium tuberculosis and Mycobacterium
avium complex) in granulomatous lesions in organs
such as skin and lungs.1721,7580 Thus, there is evidence
for mycobacteria as a cause for sarcoidosis, but also
evidence to the contrary. It also seems unlikely that
other bacteria are the cause of ES. Only one horse had
a weak positive serology titre for C. pseudotuberculosis,

59

which likely indicated a previous exposure as the PCR


was negative. Histologic features of C. pseudotuberculosis
infections are quite different from ES and are mainly
characterized by a pyogranulomatous inflammation
that may contain numerous eosinophils.81
The occasional large gram-positive narrow bacilli,
located in both granulomatous (inflamed) and noninflamed
areas were most consistent with Clostridium spp. This
finding is most likely to be caused by contamination as
these bacteria were not associated with granulomatous
changes. The organisms are also unusual in skin specimens.
Lymphocyte exocytosis, which has been described
in humans,82 was seen in one horse. Otherwise, all nine
horses presented with virtually identical lesions, including
variably sized aggregates of multinucleated histiocytic giant
cells and epithelioid cells with small numbers of neutrophils, lymphocytes and plasma cells within the superficial and deep dermis. This is similar to previous reports.5,6
In conclusion, the failure to obtain positive results
from the PCR assays and special histological stains
indicate that the granulomatous lesions associated with
ES are unlikely to be caused by persistent mycobacterial,
coccidioidal, cryptococcal, corynebacterial or Borrelia
infections. Failure to detect an infectious aetiology
because of elimination of the infectious agent(s) by
the immune system is unlikely, as the granulomatous
inflammation did not subside without treatment. This
leads to the hypothesis that the tissue reaction associated
with ES is the response to a persistent antigenic trigger
that is difficult to degrade by the host. The nature of this
trigger is still unknown and ES remains a disease of undetermined aetiology and therefore, a diagnosis of exclusion.

AC K N OW L E D G E M E N T S
The authors thank IDEXX Laboratories Inc., West
Sacramento, California for access to case material, the
late Dr Tony Stannard for pioneering most of the
initial information regarding sarcoidosis in horses and
for Figs 3, 4 and 5, Dr Thelma Lee Gross for aiding
the acquisition of cases from IDEXX and the horse
owners. Finally, the authors are thankful for resources
from the George H. Muller Fund for Research in
Veterinary Dermatology at the School of Veterinary
Medicine, University of California, Davis.

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Rsum Neuf chevauxgs de 5 21 ans ont t diagnostiqus avec une sarcoidose cutane (ES) en 18 ans. En
plus des lsions cutanes, une atteinte pulmonaire tait frquemment note, les autres organes tant moins
touchs. Une prdisposition pour les animaux de race pure tait observe. Les lsions cutanes regroupaient des
crotes, des squames, une alopcie et un prurit. Elles taient observes sur diffrentes zones, notamment les membres, les cuisses, les coudes, le thorax, le cou, la face et labdomen ventral. Trois chevaux ont t euthanasis peu
aprs lhospitalisation, dautres ont survcu jusqu 12 ans. La recherche de micro-organismes par histologie,
immunohistochimie, et PCR (pour Mycobacteria spp., Coccidioides immitis, Cryptococcus neoformans, Corynebacterium pseudotuberculosis, et Borrelia burgdorferi) tait ngative. Ltiologie de lES est peu probablement
dorigine microbienne et ce diagnostic reste un diagnostic dexclusion. LES limit la peau est de bon pronostic,
avec une rmission partielle ou complte avec une corticothrapie.
Resumen Nueve caballos de entre 5 21 aos de edad se diagnosticaron de sarcoidosis equina cutnea (ES)
durante un perodo de 18 aos. Adems de la piel, los pulmones aparecieron afectados con frecuencia, y otros
rganos con menor frecuencia. Se observ una predisposicin por caballos pura sangre y caballos castrados. Los
ndulos se presentaron en varios lugares, pero especialmente en las extremidades/muslos/codos, trax, cuello,
cara y vientre. Tres caballos se sacrificaron poco despus de ser hospitalizados, otros sobrevivieron hasta 12 aos.
Tinciones histolgicas e inmunohistoqumicas frente a Mycobacteria spp., Coccidioides immitis, Cryptococcus
neoformans, Corynebacterium pseudotuberculosis y Borrelia burgdorferi fueron negativas. La etiologa de ES posiblemente no es microbiana y contina siendo un diagnstico por exclusin. Si esta limitada a la piel, el pronstico
es generalmente favorable, con respuesta parcial o completa a la terapia de glucocorticoides en todos los caballos
supervivientes.
Zusammenfassung Neun Pferde im Alter von 5 bis 21 Jahren wurden ber einen Zeitraum von 18 Jahren mit
kutaner equiner Sarkoidose (ES) diagnostiziert. Zustzlich zur Haut war die Lunge hufig involviert, whrend
andere Organsysteme weniger hufig betroffen waren. Eine Prdisposition fr Vollblter und Wallachen wurde
festgestellt. Kutane Vernderungen und Symptome beinhalteten Krusten, Schuppen, Alopezie und Juckreiz.
Diese wurden in verschiedenen Lokalisationen gefunden, vor allem an den Extremitten/Oberschenkeln/Ellbgen,
am Thorax, Hals, Gesicht und am ventralen Abdomen. Drei Pferde wurden kurz nach der Einweisung euthanasiert;
andere berlebten bis zu 12 Jahre. Die histopathologischen Frbungen, die Immunhistochemie und die Polymerase
Chain Reaction Assays, die an den in Paraffin eingebetteten Hautproben von acht Pferden auf der Suche nach
Mycobacteria spp., Coccidioides immitis, Cryptococcus neoformans, Corynebacterium pseudotuberculosis und
Borrelia burgdorferi durchgefhrt wurden, waren alle negativ. Eine mikrobielle tiologie von ES ist unwahrscheinlich und somit bleibt ES eine Ausschlussdiagnose. Wenn die ES auf die Haut beschrnkt war, bestand eine
gute Prognose, mit entweder teilweisem oder komplettem Ansprechen auf die Glukokortikoidtherapie bei allen
berlebenden Pferden.

2006 The Authors. Journal compilation 2006 European Society of Veterinary Dermatology