sign in sign up
<<
Home , Botryomycosis, Common (horse), Crust (dermatology), Detomidine, Elephantiasis nostras, Horse sheath cleaning

IN-DEPTH: SELECTED TOPICS IN

Equine Dermatology

Stephen D. White, DVM, Diplomate ACVD; and Anthony A. Yu, DVM, MS, Diplomate ACVD

Authors’ addresses: Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California at Davis, Davis, CA 95616 (White); and Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, Ontario N1G 2W1, Canada (Yu); e-mails: [email protected] (White) and [email protected] (Yu). © 2006 AAEP.

I. Diagnosis and Treatment of the Pruritic

Pyoderma (Bacterial ) ative border as seen in dogs with superficial ; Figs. 1 and 2), or encrusted sim- Stephen D. White, DVM, Diplomate ACVD ilar to the miliary reaction pattern in .6 These infections tend to be variable in their 1. Introduction intensity of pruritus. usually shows fol- Bacterial (superficial pyoderma) is usu- liculitis and/or furunculosis, but bacterial colonies ally caused by a coagulase positive Staphylococcus are not always seen. A truncal form of bacterial . Both S. aureus and S. intermedius have folliculitis (contagious , contagious pustular been isolated.1,2 In one study, S. aureus accounted dermatitis, or Canadian horsepox) is often associ- for twice as many isolates as S intermedius; the ated with poor grooming, trauma from tack and same study isolated some strains of S. hyicus as , warm wet weather, and heavy work. It is well.3 Interestingly, in another study, lysozymes painful and interferes with working and riding. from equine neutrophils were only slightly bacteri- It is usually caused by a coagulase positive Staphy- cidal for S. aureus.4 Many isolates are resistant to lococcus species but may also be caused by Coryne- G3. Occurrence of pyoderma has been bacterium pseudotuberculosis.7 This organism is linked to poor nutrition and husbandry in some more commonly a cause of deep pyoderma, as dis- cases.5 cussed below (Fig. 3). In , folliculitis often Clinical signs of staphylococcal pyoderma are develops in the saddle and lumbar region, particu- most often crusts, usually in a circular pattern sug- larly in the summer. The affected area initially gestive of (this may be the reason may be swollen and very sensitive; this is followed that equine pyoderma is underdiagnosed), epider- by formation of follicular papules and pustules. mal collarettes (circular skin with an exfoli- These may become confluent or rupture, forming

NOTES

AAEP PROCEEDINGS ր Vol. 52 ր 2006 457 IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY

Fig. 3. pseudotuberculosis folliculitis: circu- lar areas of and alopecia. (Courtesy of Elsevier Publish- ing.)

Fig. 1. Staphylococcal folliculitis: crusts in a circular pattern. (Courtesy of Elsevier Publishing.) painful. The is usually not associated with systemic signs, and the general health of the horse is not affected. plaques and crusts. Deep pyoderma followed by A relatively uncommon nodular disease termed ulceration may develop over large areas of the body, “” mimics or a deep fun- especially on the neck, sides of the thorax, inner gal , but it is most often caused by Staphy- surface of the thighs, or the prepuce. lococcus species in the horse. These may require A pastern bacterial infection (pastern folliculitis) surgical excision as well as long-term . is often seen. Again, the causative agent is usually .Public Health Considerations؊Staphylococcus spp .2 a coagulase positive Staphylococcus species. As with most “primary ,” the mechanism(s) In a 2000 study, methicillin-resistant coagulase- negative staphyloccal species were cultured from whereby the organism gains its foothold is unknown 8 (not contagion and not poor sanitary conditions). healthy horses in Japan; Yusada et al. concluded The lesions are usually limited to the posterior as- that “[t]hese organisms must be considered a poten- pect of the pastern and fetlock regions; one or more tial threat to horses and veterinarians who care for limbs may be involved. The initial lesions consist them.” In a 2006 study from the Netherlands, me- thicillin-resistant coagulase-negative staphylococci of papules and pustules (Fig. 4). If left untreated, 9 the lesions coalesce and may produce large areas of were found frequently. The organism was usually ulceration and suppuration, which may be quite S. sciuri, not S. epidermidis, which was found in the humans in close contact with these horses. No me- thicillin-resistant S. aureus (MRSA) was found in healthy horses. In contrast, a single strain of MRSA was isolated from both humans (13%) and horses (4.7%) on horse farms in Canada and New York state.10 In looking at horses admitted to a university teaching hospital (Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada), MRSA was isolated from 120 (5.3%) of 2,283 horses. Of these 120 horses, 50.8% were positive at the time of admission, and clinical infections attributable to MRSA were present or developed in 14 horses. Horses colo- nized at admission were more likely to develop clin- ical MRSA infection. Administration of ceftiofur or aminoglycosides during hospitalization was the only risk factor associated with nosocomial MRSA colo- nization. Another strain of MRSA was isolated Fig. 2. Staphylococcal folliculitis: widespread, coalescing ar- from a small number of horses at the Veterinary eas of alopecia and scaling. (Courtesy of Elsevier Publishing.) University in Vienna, Austria.11

458 2006 ր Vol. 52 ր AAEP PROCEEDINGS IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY resistance to trimethoprim-sulfa drugs, enrofloxacin may be used. Use of enrofloxacin in young horses (Ͻ2 yr old) should be avoided because of concerns of damage to the articular cartilage.14 A recent re- port15 on the use of an oral-gel formulation of enro- floxacin (100 mg/ml of gel) showed good clinical efficacy for infections in several organs; however, almost one-third of the horses had some diarrhea, and 10% had oral lesions. Epstein et al.15 felt that this latter side effect could be overcome with admin- istration of tap water rinse of the oral cavity. In- terestingly, enrofloxacin binds to melanin in equine , although the clinical implication is unknown.16 In one report of 15 horses, vancomycin was used, alone or in combination with an aminoglycoside, to treat MRSA and enterococcal infections. The aver- age vancomycin dosage was 7.5 mg/kg,q8h,IVover 30 min. The , alone or in combination with an aminoglycoside, was safe and effective. Because of the problems with emerging resistance, Orsini et al.17 recommended that the use of vanco- mycin in horses be limited to cases in which culture and susceptibility indicate effectiveness and no rea- sonable alternative treatment is available. For localized lesions, generic mupirocin ointment 2% or creama may be effective. Shampoos such as ethyl lactateb or chlorhexidine (2%–4%) are helpful. Dermatophilosis is caused by an actinomycete Dermatophilus congolensis. Three condi- tions must be present for Dermatophilus to manifest itself: a carrier animal, moisture, and skin abra- sions. Chronically affected animals are the pri- mary source of infection. However, they only become a serious source of infection when their le- sions are moistened. This results in the release of zoospores, the infective stage of the organism. Me- chanical transmission of the disease occurs by both biting and non-biting flies and possibly, fomites. Because normal healthy skin is quite impervious to Fig. 4. Pastern folliculitis. (Courtesy of Elsevier Publishing.) infection with D. congolensis, some pre-disposing factor that results in decreased resistance of the skin is necessary for infection to occur; prolonged wetting of the skin by rain is one of the most prev- Of most concern is the finding of humans report- alent causes. ing skin lesions after contact with a community The disease is usually seen during the fall and MRSA-positive affected foal, despite short-term con- winter months with the dorsal surface of the animal tact with standard protective barriers. The isolates most commonly affected. Occasionally, the lesions from the foal were indistinguishable from the ones involve the lower extremities when animals are kept from the humans.12 in “wet pastures” (“dew poisoning”) or if horses are left in the stall while the stall is cleaned with high- 3. Treatment of Equine Pyoderma pressure water hoses. In the early stages of the The antibiotic usually used for many bacterial skin disease, the lesions can be felt better than they can infections in the horse is trimethoprim sulfa orally be seen. Thick crusts can be palpated under hair (30 mg/kg, q 12 h for 2–6 wk, longer for deep infec- (Fig. 5). Removing the crusts and attached tions).6 Interestingly, dosing intervals for IV ad- hair exposes a pink, moist skin surface with both the ministration of trimethoprim-sulfamethoxazole in removed hair and the exposed skin assuming the horses may not be appropriate for use in donkeys or shape of a “paintbrush.” The under surface of the . Donkeys eliminate the drugs rapidly com- crusts are usually concave with the roots of the pared with horses.13 In cases of Staphylococcus sp. protruding.

AAEP PROCEEDINGS ր Vol. 52 ր 2006 459 IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY

Fig. 7. Dermatophytosis: circular alopecia and scaling caused Fig. 5. Dermatophilosis: severe scaling and alopecia. (Cour- by Trichophyton mentagrophytes infection. (Courtesy of tesy of Dr. V. Fadok and Elsevier Publishing.) Elsevier Publishing.)

Diagnosis is made by the “railroad track” cocci on rum, and degenerating neutrophils is the most char- impression smears: a portion of one of the crusts acteristic change. A superficial folliculitis may be a should be minced and mixed with a few drops of prominent feature of the disease.1 In sections sterile water on a glass slide, gram stained, and stained with gram stain, the branching, filamentous examined microscopically (Fig. 6). Alternatively, organisms can be observed in the crusts and in the bacterial culture or histopathology may be used for follicles. Treatment is removal from the wet envi- diagnosis. A thick crust composed of alternating ronment, removal of crusts (with care because these layers of parakeratotic , dried se- may be painful), washing with iodophors or lime , and use of antibiotics (penicillin at 22,000 mg/kg procaine pen G, q 12 h, IM or trimethoprim sulfa orally with the same dosage used for staphy- lococcal pyoderma) for 7 days.18 As the crusts are important in contagion, these should be disposed of rather than brushed on to the ground.

4. and Malassezia infections, like pyoderma, can be variably pruritic. The most common equine der- matophyte species isolated from horses are Tricho- phyton equinum, M. equinum, T. mentagrophytes, and T. verrucosum.1,3,19 Tack (, halters, and saddle blankets) often act as fomites. The lesions usually appear first on the axillary/girth area and may spread over the trunk, rump, neck, head, and limbs (Fig. 7). Initial lesions may be urticarial in nature and can progress to multi-focal, sharply de- marcated scaling and crusting areas (Figs. 8 and 9). Lesions may be superficial or deep. Superficial in- fections are more common and are manifested by the development of thick crusts or more generally, a diffuse moth-eaten appearance with and alopecia. Less commonly, deeper structures are infected through the hair follicles, which causes small foci of inflammation and suppuration. A small crust forms over the follicle, and the hair is lost. However, extensive alopecia and crust forma- Fig. 6. Dermatophilosis: branching chains of cocci (“railroad tion do not occur; some irritation and itching may be tracks”) modified Wright’s stain times 100. (Courtesy of Dr. V. caused by this type. Rarely, dermatophytosis may Fadok and Elsevier Publishing) be limited to the coronary band (Fig. 10).

460 2006 ր Vol. 52 ր AAEP PROCEEDINGS IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY

Fig. 10. Dermatophytosis: scaling of the coronary band caused by Microsporum gypseum infection. (Courtesy of Dr. V. Fadok and Elsevier Publishing.)

Fig. 8. Dermatophytosis: urticarial lesions caused by Tricho- phyton mentagrophytes infection. (Courtesy of Elsevier Publish- cially at the advancing periphery of an active, non- ing.) medicated . In addition, surface may be gathered by forceps or skin scrapings from simi- lar areas and inoculated onto the culture medium. The hair and surface keratin of large animals have large numbers of saprophytic fungi and bac- Diagnosis is by fungal culture; biopsy is less reli- teria. Therefore, it is recommended by some cli- able (Trichophyton species may cause , 20 nicians to cleanse the skin before taking samples which mimics on histopathology). for culture. This may be done by gently cleansing Hair is the specimen most commonly collected for the area to be sampled with water and allowing it the isolation of dermatophytes. Using forceps, to air dry, although the authors do not routinely hairs should be selected that appear broken, espe- do this. Sabouraud’s dextrose agar has been used tradi- tionally in veterinary mycology for the isolation of fungi; however, other media are available with bacterial and fungal inhibitors, such as dermato- phyte test medium (DTM). DTM is essentially Sabouraud’s dextrose agar containing cyclohexi- mide, gentamicin, and chlortetracycline as anti- fungal and antibacterial agents and to which the pH indicator phenol red has been added. Der- matophytes use protein in the medium first, and alkaline metabolites turn a medium red. Most other fungi use carbohydrates first and give off acid metabolites, which do not produce a red color change. These saprophytic fungi will later use the protein in the medium, resulting in a red color change. However, this usually occurs only after a prolonged incubation (10–14 days or more). Con- sequently, DTM cultures should be examined daily for the first 10 days. Some Aspergillus spe- cies and others cause a red color change in DTM, and therefore, microscopic examination is essen- tial to avoid an erroneous presumptive diagnosis. It has been recommended that 1–2 drops of a sterile injectable B complex vitamin preparation Fig. 9. Dermatophytosis: urticarial lesion caused by Tricho- be added to culture plates when culturing horses, phyton mentagrophytes infection that transitions into a circular because one strain of T. equinum (T. equinum area of alopecia. (Courtesy of Elsevier Publishing.) var. equinum) has a unique niacin requirement.

AAEP PROCEEDINGS ր Vol. 52 ր 2006 461 IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY However, the authors do not routinely do this. Skin scrapings and hair should be inoculated onto Sabouraud’s dextrose agar and/or DTM and incu- bated at 30°C with 30% humidity. A of water in the incubator will usually provide enough hu- midity. Cultures should be checked every day for growth. DTM may be incubated for 21 days, but cultures on Sabouraud’s agar should be allowed 30 days to develop. The authors usually use Derm- Duet,c which has DTM on one side, rapid sporu- lating media (RSM) on the other side, and a well of water in the center. It is routinely incubated at room temperature. T. verrucosum has been re- ported not to grow on DTM.21 Topical treatment alone is often cura- tive. Although 50% captan (2 tablespoons of the powder in 1 gallon of water) has been touted in the Fig. 11. Cytology of Malassezia sp. from intermammary debris past, and while certainly safe for tack, its effective- from a healthy mare. (Courtesy of Elsevier Publishing.) ness has been questioned. Lime Sulfurd (1 cup to 1 gallon of water) or bleach (1:10 with water) are both effective but messy and odiferous. Miconazole or culture as Malassezia species (Fig. 11). Treatment ketoconazole veterinary shampoos are becoming with a topical 2% miconazole/chlorhexidine shampoo more widely used and may be as effective. In Eu- e was curative. The authors are aware of other sim- rope and Canada, an enilconazole rinse is highly ilar cases. However, healthy non-pruritic mares effective. may also have large numbers of yeasts in the intra- Systemic treatment is occasionally need- mammary area.28 ed. Griseofulvin’s efficacy in horses (as well as an effective dose) has not been thoroughly re- References and Footnotes searched. However, a dosage of 100 mg/kg daily 1. Scott DW, Manning TO. Equine folliculitis and furunculo- for 7–10 days has been advocated and has been sis. Equine Pract 1980;2:11–32. used with good success on a small number of 2. Shimizu A, Kawano J, Ozaki J, et al. Characteristics of isolated from lesions of horses. J Vet horses by the authors. Griseofulvin is a terato- Med Sci 1991;53:601–606. gen and should not be used in pregnant mares. 3. Chiers K, Decostere A, Devriese LA, et al. Bacteriological Additionally, it is no longer available. Alterna- and mycological findings, and in vitro antibiotic sensitivity of tively, 20% NaI may be given IV (250 ml/500 kg pathogenic staphylococci in equine skin infections. Vet Rec horse every 7 days, 1–2 times). This also is con- 2003;152:138–141. 4. Pellegrini A, Waiblinger S, Von Fellenberg R. Purification of traindicated in pregnant mares, because it may equine neutrophil lysozyme and its antibacterial activity cause abortion. Although such as against gram-positive and gram-negative bacteria. Vet Res itaconazole and fluconazole have been used to Commun 1991;15:427–435. treat horses with systemic mycotic infections such 5. Inokuma H, Kanaya N, Fujii K, et al. Equine pyoderma associated with malnutrition and unhygienic conditions due as and aspergillosis, there to neglect in a herd. J Vet Med Sci 2003;65:527–529. have not been any studies on their effectiveness in 6. White SD. Equine bacterial and fungal skin : dermatophytosis. However, the safety record in a diagnostic and therapeutic update. Clin Tech Equine horses in the face of the doses used (2–5 mg/kg, q Pract 2005;4:302–310. 12 h) are encouraging.22–24 Vaccination to T. 7. Heffner KA, White SD, Frevert CW, et al. Corynebacterium folliculitis in a horse. J Am Vet Med Assoc 1988;193:89–90. equinum may reduce the incidence of new infec- 8. Yasuda R, Kawano J, Onda H, et al. Methicillin-resistant tions and protect a high percentage (Ͼ80%) of coagulase-negative staphylococci isolated from healthy vaccinates from infection. This data is based on horses in Japan. Am J Vet Res 2000;61:1451–1455. results with an inactivated containing 9. Busscher JF, van Duijkeren E, Sloet van Oldruitenborgh- 25 Oosterbaan MM. The prevalence of methicillin-resistant both conidia and mycelial elements. staphylococci in healthy horses in the Netherlands. Vet Mi- The exact species of Malassezia growing on horses’ crobiol 2006;113:131–136. skin is just beginning to be investigated.26 In one 10. Weese JS, Rousseau J, Traub-Dargatz JL, et al. Commu- study, the Malassezia sp. isolated were identified as nity-associated methicillin-resistant Staphylococcus aureus M. furfur, M. slooffiae, M. obtusa, M. globosa, and M. in horses and humans who work with horses. J Am Vet Med 27 Assoc 2005;226:580–583. restricta. The authors have examined several 11. Cuny C, Kuemmerle J, Stanek C, et al. Emergence of MRSA mares with Malassezia infections between their infections in horses in a veterinary hospital: strain charac- mammary that were intensely pruritic. terisation and comparison with MRSA from humans. Eur The mares rubbed their and ventral abdomens. Surveill 2006;11:44–47. 12. Weese JS, Caldwell F, Willey BM, et al. An outbreak of Physical examinations showed dry, greasy-to-the- methicillin-resistant Staphylococcus aureus skin infections touch exudate. Cytology of the exudate showed nu- resulting from horse to human transmission in a veterinary merous yeast organisms, which were identified on hospital. Vet Microbiol 2005;114:160–164.

462 2006 ր Vol. 52 ր AAEP PROCEEDINGS IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY

13. Peck KE, Matthews NS, Taylor TS, et al. Pharmacokinetics of sulfamethoxazole and trimethoprim in donkeys, mules, and horses. Am J Vet Res 2002;63:349–353. 14. Egerbacher M, Edinger J, Tschulenk W. Effects of enro- floxacin and ciprofloxacin hydrochloride on canine and equine chondrocytes in culture. Am J Vet Res 2001;62:704–708. 15. Epstein K, Cohen N, Boothe D, et al. Pharmacokinetics, stability, and retrospective analysis of use of an oral gel formulation of the bovine injectable enrofloxacin in horses. Vet Ther 2004;5:155–167. 16. Dunnett M, Richardson DW, Lees P. Detection of enrofloxa- cin and its metabolite ciprofloxacin in equine hair. Res Vet Sci 2004;77:143–151. 17. Orsini JA, Snooks-Parsons C, Stine L, et al. Vancomycin for the treatment of methicillin-resistant staphylococcal and en- terococcal infections in 15 horses. Can J Vet Res 2005;69: 278–286. 18. Outerbridge CA, Ihrke PJ. Folliculitis: staphylococcal pyoderma, dermatophilosis, dermatophytosis. In: Robin- son NE, ed. Current therapy in equine medicine, 5th ed. St. Fig. 1. Culicoides is the insect most commonly associated with Louis: W.B. Saunders, 2003;197–200. insect bite hypersensitivity/sweet . 19. Kane J, Padhye AA, Ajello L. Microsporum equinum in North America. J Clin Microbiol 1982;16:943–947. 20. Scott DW. Marked acantholysis associated with dermato- phytosis due to Trichophyton equinum in two horses. Vet Dermatol 1994;5:105–110. 21. Scott DW, Miller WH. Equine dermatology. St. Louis: 2. An immediate (i.e., type 1) hypersensitivity W.B. Saunders, 2003;96. to salivary antigens of biting insects or inhala- 22. Foley JP, Legendre AM. Treatment of coccidioidomycosis tion of desiccated insects, which is supported osteomyelitis with itraconazole in a horse. A brief report. by the increased immunohistochemical J Vet Int Med 1992;6:333–334. 23. Korenek NL, Legendre AM, Andrews FM, et al. Treatment presence of IgE in skin of horses with insect of mycotic with itraconazole in three horses. J Vet hypersensitivity and detection of IgG and IgE Int Med 1994;8:224–227. serum to Culicoides salivary 24. Taintor J, Crowe C, Hancock S, et al. Treatment of conid- antigens in horses with insect dermal iobolomycosis with fluconazole in two pregnant mares. J Vet 1,2 Int Med 2004;18:363–364. hypersensitivity. 25. Pier AC, Zancanella PJ. Immunization of horses against 3. A delayed (i.e., type 4) and cutaneous baso- dermatophytosis caused by Trichophyton equinum. Equine phil hypersensitivity reaction that is similar Pract 1993;15:23–27. to flea- dermatitis in dogs and cats. 26. Nell A, James SA, Bond CJ, et al. Identification and distri- 4. Langerhans’ cells and T-lymphocytes cyto- bution of a novel Malassezia species yeast on normal equine 3–5 skin. Vet Rec 2002;150:395–398. kine production. 27. Crespo MJ, Abarca ML, Cabanes FJ. Occurrence of Malassezia spp. in horses and domestic ruminants. Mycoses Ultimately, all of the above cells interact to enhance 2002;45:333–337. release of inflammatory that result in eo- 28. White SD, Vandenabeele SIJ, Drazenovich N, et al. Malassezia species isolated from the intermammary and pre- sinophil recruitment and activation. Culicoides putial fossa areas of horses. J Vet Int Med 2006;20:395–398. spp., black flies, horn flies, and stable flies most commonly implicated, and occasionally, mosquitoes, aSilvadene, Monarch Pharmaceuticals, Inc., Bristol, TN 37620. deer flies, and horse flies are involved (Fig. 1). bEtiderm, VIRBAC, Ft. Worth, TX 76137. c DermDuet, Bacti-Labs, Mountain View, CA 94042. 2. Signalment dLymDyp, Miami, FL 33169. eImaveral, Janssen-Cilag Animal Health 1 rue Camille, Des- The tendency to develop insect hypersensitivity moulins, France. seems to be multifactorial (, major histocom- patibility complex, and geography). Evidence ex- ists that insect hypersensitivity reactions may be 35% inherited.3 Certain breeds (i.e., Welsh Ponies, Icelandics, Arabians, Connemaras, Quarter Horses, Insect Hypersensitivity and German Shires) seem to be predisposed to de- veloping insect hypersensitivity. Many horses Anthony A. Yu, DVM, MS, Diplomate ACVD start to develop clinical signs at a young age (i.e., 2–4 yr).3,6,7 1. Introduction Insect hypersensitivity is the most common cause of 3. Clinical Signs equine pruritus. There are four contributing Generally, most cases of insect hypersensitivity tend causes of pruritus. to be seasonal (in areas where colder weather affects insect development), be highly pruritic (somewhat 1. The bite itself, which is painful because of steroid unresponsive depending on severity), and the chewing mouthparts of these flies. begin with primary papules or wheals involving a

AAEP PROCEEDINGS ր Vol. 52 ր 2006 463 IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY

Table 1. Parasite Information for Insects That Cause Equine Hypersensitivity Reactions12

Environmental Condition Necessary Type of Insect Feeding Location Time of Feeding for Insect Reproductive Survival

Culicoides spp Depends on species Sunrise and sunset Standing water Dorsal (mane and ) Decaying vegetation Ventrum Manure Both No lesions on the lateral thorax in US horses Blackflies Face Morning and evening Running water Ears Ventral abdomen Groin Medial forelegs Thighs Stable flies Legs Daytime, under shade trees Manure Abdomen Prefer the early morning and Decaying bedding late evening Horn flies Focal midline (around the Daytime Cow manure umbilicus) Mosquitoes Lateral aspect of the body Dusk Water Immediately after sunset Deerflies Sides of chest Daytime Vegetation Flanks and proximal legs Water Horseflies Sides of chest Daytime Vegetation Flank and proximal legs Water

dorsal or ventral distribution and a combination “buzzed mane” and “rat tail” appearance, respec- distribution pattern depending on the feeding habits tively (Fig. 4). Secondary Staphylococcus infec- of the insects involved (e.g., Culicoides pusillus tions are common and may exacerbate the pruritus. [mane/tail], C. lahillei [ventral], C. alachua [dorsal], Black flies are known to have a salivary toxin C. insignis [all of the above]; Table 1).8 Second- that, when injected repeatedly (i.e., multiple bites), arily, alopecia, crusting, excoriations, hypopigmen- tation, and lichenification occur as a result of chronic irritation (Figs. 2 and 3). When pruritus involves the mane and tail, the horse will rub the areas until the hairs are broken or barbed, leaving a

Fig. 2. Classic distribution of a severe case of insect-bite hyper- sensitivity encompassing all described distribution patterns in- Fig. 3. Severe case of insect bite hypersensitivity with crust and cluding mane/tail, dorsum, and ventrum. post-inflammatory hypopigmentation involving the inner thighs.

464 2006 ր Vol. 52 ր AAEP PROCEEDINGS IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY

Fig. 5. Trans-illuminated positive intradermal reactions to in- sect in a horse with suspected insect bite hypersensi- tivity.

. Other ectoparasites such as lice, Chorioptes, and Psoroptes should be ruled out be- fore pursuing extensive diagnostics.

5. Diagnosis Diagnosis of insect hypersensitivity is based on his- tory (single horse involvement and seasonality; e.g., spring [C. niger/alachua], summer [C. stellifer], and fall [C. insignis] depending on the region), distribu- tion pattern (e.g., horn flies focus on the umbilical region), and an inspection of the patient’s environ- ment for evidence of insect breeding grounds (for- Fig. 4. Characteristic rubbed tail of a horse with insect-bite ested area or ponds/still water within a mile; Table hypersensitivity. 1). Skin scrapings are helpful in ruling out ecto- parasite problems (e.g., Chorioptes and psoroptes). Skin cytologies and/or cultures are useful in deter- mining whether a bacterial (Staphylococcus or Der- is capable of causing capillary permeability leading matophilus) and/or fungal infection (Trichophyton to shock and even death.6 Horsefly and deerfly mentagrophytes, Microsporum canis,orMicrospo- bites differ from those of other insects in that they rum gypseum) is present. typically cause nodular lesions that ulcerate.3,6 There are diagnostic tests for insect hypersensi- Respiratory signs (i.e., recurrent airway obstruction tivity. that is similar to reactions noted in humans with asthma and arthropod hypersensitivity) have been 1. A stringent ectoparasiticidal trial using associated with positive skin-test reactions to only Knockout L.A.a up to every other day de- Culicoides spp. and mosquitoes.7,9,10 pending on the severity of the condition and parasite load in the environment. One 4. Differential Diagnoses study noted significant improvement with The primary differentials for insect hypersensitiv- every other week application in cases of sus- ity include atopy, , and a stable vice. pected Culicoides hypersensitivity.11 Secondary bacterial infections are common. Pri- 2. Intradermal skin testing with several insects mary or secondary dermatophytosis should always including Culicoides variipennis, which be considered, particularly if multiple horses are crossreacts with other species of Culicoides, affected in the same environment. Some species stable flies, mosquitoes, deer flies, horse flies, (e.g., C. variipennis) transmit the filarid parasite, and black flies, because several types of in- Onchocerca cervicalis, which in itself may result sects can cause in horses; however, in similar clinical signs with ventral crusting/pru- many have cross-reactive antigens (Fig. ritus. A regular deworming protocol with iver- 5).3,6,7,12–14 mectin would minimize the likelihood of 3. In vitro testing is not reliable in horses.15

AAEP PROCEEDINGS ր Vol. 52 ր 2006 465 IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY 4. is supportive but not con- Atopy clusive of insect hypersensitivity.3,6 Anthony A. Yu, DVM, MS, Diplomate ACVD 6. Conclusion Insect hypersensitivities can manifest as a single 1. Introduction condition or as part of a spectrum of allergic condi- Manifestations of equine allergies include derma- tions including atopy, food allergy, and contact hy- toses (, pruritus, scale/crust, leukotrichia, or persensitivity. To successfully manage any equine nodules) as well as respiratory conditions (recur- patient with allergies, every effort should be made to rent airway obstruction [RAO]). Currently, the become familiar with the feeding habits and envi- pathomechanism is not completely understood ronmental requirements for reproduction for in- both in human and veterinary medicine. Aller- sects. This will help to successfully eliminate their gies seem to be a multifactorial condition involv- contribution to the load. ing immunoglobulins, major histocompatibility complex (MHC-II), cytokines, chemokines, and the References and Footnote neuroendocrine system. The classic type I hyper- 1. van der Haegen A, Griot-Wenk M, Welle M, et al. Immuno- sensitivity pathway continues to play an intrinsic globulin-E-bearing cells in skin biopsies of horses with insect role in the production of an allergic response. bite hypersensitivity. Equine Vet J 2001;33:699–706. 2. Wilson AD, Harwood LJ, Bjornsdottir S, et al. Detection of The inherited predisposition to form sensitizing IgG and IgE serum antibodies to Culicoides salivary gland antibodies to environmental allergens such as antigens in horses with insect dermal hypersensitivity (sweet molds, dust, and pollens of grasses, weeds, and itch). Equine Vet J 2001;33:707–713. trees results in the production of antigen specific 3. Scott DW, Miller WH. Insect hypersensitivity. In: Scott immunoglobulin E (IgE), which then fixes to tissue DW, Miller WH, eds. Equine dermatology. Philadelphia: W.B. Saunders, 2003;458–467. mast cells. Cross linking of bound IgE 4. Kurotaki T, Narayama K, Arai Y, et al. Langerhans cells results in release of inflammatory mediators, within the follicular and the intradermal sweat which culminates in pruritus, urticaria, and an duct in equine insect hypersensitivity “Kasen.” J Vet Med allergic bronchitis. Other genes, such as the beta Sci 2002;64:539–541. 5. McKelvie J, Foster AP, Hamblin AS, et al. Culicoides anti- chain of the high affinity IgE receptor found on gen extract stimulates equine blood mononuclear (BMN) cell mast cells and basophils, may also regulate sus- proliferation and the release of eosinophil adherence-induc- ceptibility to atopy. We now realize that this tra- ing factor(s). Res Vet Sci 2001;70:115–122. ditional type-I allergic response is only the tip of 6. Pascoe R, Knottenbelt DC. Immune-mediated/allergic dis- the iceberg, and its role still remains controversial eases. In: Pascoe R, Knottenbelt DC, eds. Manual of equine 1–3 dermatology. London: W.B. Saunders, 1999;155–181. in the horse, especially in cases of RAO. 7. Fadok VA. Update on equine allergies. Vet Allergy Clin In humans, the allergic response has been further Immunol 1997;15:69–76. elaborated to involve T lymphocytes, particularly 8. Greiner EC, Fadok VA, Rabin EB. Equine culicoides hyper- the T helper cell paradigm. The T helper 2 cell sensitivity in Florida: biting midges aspirated from horses. Med Vet Entomol 1990;4:375–381. (Th2), in fact, produces cytokines such as interleu- 9. Baur X, Liebers V. Insect immunoglobulins (Chi t I) of the kins (IL) 4, 5, 6, 10, and 13, of which IL4 and IL13 Diptera chironomus are relevant environmental, occu- are essential for the B-cell immunoglobulin class pational and hobby-related allergens. Int Arch Occup Envi- switching to IgE. In non-atopic individuals, the T ron Health 1992;64:185–188. helper 1 cell line (Th1) produces interferon (IFN) 10. Bernton HS, Browne H. Insect allergy: preliminary stud- ies of the cockroach. J Allergy Clin Immunol 1992;25:506– and IL2, which in turn suppress the proliferation of 513. allergy promoting Th2 cells, and are responsible for 11. Bourdeau PJ, Beis C, Chouilly C, et al. Evaluation of per- the local immune defense system. methrin and pyriproxyfen containing spray in the treatment Recently, bronchoalveolar lavage fluid harvested of sweet itch in 25 horses, in Proceedings. 15th Annual Member’s Meeting of the American Academy of Veterinary from antigen challenged allergen induced RAO Dermatology/American College of Veterinary Dermatology horses had increased numbers of Th2 cells that pro- 1999;13–14. duced the classic allergic profile (increased IL4 and 12. Rees C. Diagnosing and managing equine pruritus: insect IL5 and decreased IFN).4 Many studies show the hypersensitivity. Compend Cont Educ Pract Vet 2005;27: horse’s ability to react to allergens introduced intra- 629–636. 13. Morris DO, Lindborg S. Determination of ‘irritant’ thresh- dermally; however, controversy surrounds the sig- 5–13 old concentrations for intradermal testing with allergenic nificance of these reactions. It is obvious that insect extracts in normal horses. Vet Dermatol 2003;14:31– further studies are necessary to delineate the aller- 1436. gic behavior of the equine . 14. Grier TJ, Willis EL, Esch RE, et al. Canine insect hyper- sensitivity: immunochemical evidence for common or cross- 2. Signalment reactive antigens. Vet Dermatol 1994;5:129–130. 15. Lorch G, Hillier A, Kwochka KW, et al. Comparison of im- Two recent studies from California revealed a me- mediate intradermal test reactivity with serum IgE quanti- dian age of onset of 5–6.5 yr of age with a range of tation by use of a radioallergosorbent test and two ELISAs in 2–12 yr.14,15 Cannon cautions that horses are often horses with and without atopy. J Am Vet Med Assoc 2001; 218:1314–1322. sold during the “good” season and develop allergies their next “bad” season, which makes age of onset aKnockout L.A., Virbac, Peakhurst, NSW 2210, . difficult to determine. As well, pre-disposed breeds

466 2006 ր Vol. 52 ր AAEP PROCEEDINGS IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY include , Quarter Horses, Warm- bloods, Arabians, and Morgans, and males (usually ) were almost twice as likely as mares to have atopy. However, the study populations were small, regional, and potentially, socio-economically influenced. It will take a multicenter (general and referral practice) study or verifiable survey of thou- sands of allergic horses to get a true picture of the signalment of equine allergic dermatoses.

3. Clinical Signs Pruritus with secondary lesions (alopecia, excoria- tions, lichenification, and hypopigmentation) of the face, ears, trunk, and distal legs is one presentation for equine atopy (Figs. 1–4).12–15 Horses may de- velop secondary pyoderma, which is characterized by excess scaling, small epidermal collarettes, or encrusted papules (“miliary dermatitis”). Chronic recurrent urticaria, which may or may not be pru- ritic, and allergic-based RAO, similar to that of asthma in humans and cats, may either present singly or in combination with the pruritic form. Some uncommon presenting signs suspected associ- ated with allergies include laminitis and head Fig. 2. Horse with severe housed in a high 16 tossing. allergen load environment exhibiting classic secondary lesions (alopecia and excoriation) and distribution pattern including the 4. Diagnosis face. Diagnosis of atopic dermatitis is based on history, clinical signs, and the exclusion of other differen- tials. Skin testing should not be used to diagnose 5. Intradermal Allergy Test or Blood Test atopy. Rather, allergy testing is currently used If possible, intradermal allergy testing (IDT) is pre- to discern specific environmental reactants for in- ferred over serologic allergy testing (SAT). Skin corporation into an avoidance program or inclu- testing assesses tissue fixed IgE and the entire in- sion into allergen-specific (ASIT). flammatory cascade. Because mast cells have been Positive reactions indicate that antigen-specific found to produce IL4 and express the ligand for IgE is present in the patient; it does not indicate CD40, they can then augment B cell production of that the antigen in question caused the disease. antigen specific IgE in tissues without systemic Therefore, careful historical evaluation and corre- (blood) levels being significantly increased (previ- lation with reactions will improve avoidance and ASIT success rates.

Fig. 3. Horse with severe atopic dermatitis housed in a high allergen load environment exhibiting classic secondary lesions (alopecia and excoriation) and distribution pattern including the Fig. 1. Atopic horse exhibiting pruritus by biting at its forearm. neck.

AAEP PROCEEDINGS ր Vol. 52 ր 2006 467 IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY canine IgE free samples and samples from non-al- lergic dogs.20 As well, background (non-specific) binding, lack of standardization among the various company protocols, allergenic extract preparation, incubation, washing, and blocking steps may result in aberrant reactions. At this time, the author is investigating the use of concurrent IDT and SAT techniques but relies pri- marily on the findings of the IDT, in conjunction with the historical evaluation, to determine which antigens to include in a patient’s allergen specific immunotherapy set.

6. Intradermal Allergy Testing: The Procedure Before allergy testing, the author prefers the follow- ing withdrawal periods from anti-inflammatory medications.

1. Essential fatty acids, , and topical steroids—14 days. 2. Oral glucocorticoidsϪ28 days.

Fig. 4. Horse with severe atopic dermatitis housed in a high Although appropriate withdrawal seems almost es- allergen load environment exhibiting classic secondary lesions sential in dogs and cats to obtain reactions to test (alopecia and excoriation) and distribution pattern including the allergens, testing horses on shorter to no with- chest. drawal times has, in most cases, still produced sig- nificant findings. The IDT is typically performed under sedation using detomidine.e An area for testing is shaved on the neck tailored to the amount of allergens being ously activated B cells but not naive B cells). This tested for the specific geographic region. Horses increase in antigen specific IgE in tissue after aller- with short, summer may be circumvented if gen exposure is readily identified by IDT but not 17,18 the owners are concerned about appearances during serum testing. In fact, comparison of allergen- the show season. Allergens from a typical dog/ specific IgE levels in the blood and bronchoalveolar profile along with several other insects and outdoor lavage fluid (BALF) of asymptomatic and symptom- allergens are injected intradermally in a grid pat- atic RAO horses with those of normal horses re- tern avoiding any primary or secondary existing le- vealed no difference in blood levels of allergen- sions. Skin test reactions are then assessed at 30 specific IgE. RAO horses, however, had statistically min and 4 h after inoculation. Reactions are com- significant increases of allergen specific IgE in their pared with a positive and negative control based on BALF compared with normal horses, which indicates the size and turgidity of wheals. as a a local amplification of IgE without a parallel repre- 17 criterion is limited to those horses with white skin sentation in the serum. on the neck. Based on a series of studies, horses with atopic As allergies become a more common presenting dermatitis, recurrent urticaria, and RAO generally complaint in equine medicine and long-term control have a higher incidence of positive reactions than 6–8 of symptoms using anti-inflammatory healthy horses. That being said, several studies carries side effects, costs, and drug-testing liabili- reveal that defining appropriate test concentrations ties, offering intradermal allergy testing and devel- of the allergen extracts still requires further study 5,10,19 opment of allergen-specific immunotherapy should to uniformly standardize the IDT. be a serious consideration for large equine groups/ Although the author commonly uses a combina- centers. False positive/negative reactions can be tion of IDT and SAT in his canine and feline allergic minimized by the expertise of the allergist. patients, equine serologic allergy tests thus far do not seem to reliably detect allergen hypersensitivi- ty.6 Several laboratories offer equine SAT includ- References and Footnotes ing Heska Corporation,a Greer Laboratories,b 1. Rufenacht S, Marti E, von Tscharner C, et al. Immuno- Biomedical Laboratory,c and Spectrum Laborato- globulin E-bearing cells and mast cells in skin biopsies of d horses with urticaria. Vet Dermatol 2005;16:94–101. ries. A recent study evaluating the reliability of 2. van der Haegen A, Griot-Wenk M, Welle M, et al. Immuno- canine SAT from several laboratories revealed up- globulin-E-bearing cells in skin biopsies of horses with insect wards of 30% false-positive reactions detected from bite hypersensitivity. Equine Vet J 2001;33:699–706.

468 2006 ր Vol. 52 ր AAEP PROCEEDINGS IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY 3. van der Haegen A, Ku¨ nzle F, Gerber V, et al. Mast cells and Treatment of Equine Allergies IgE-bearing cells in lungs of RAO-affected horses. Vet Im- munol Immunopathol 2005;108:325–334. Anthony A. Yu, DVM, MS, Diplomate ACVD 4. Cordeau ME, Joubert P, Dewachi O, et al. IL-4, IL-5 and IFN-gamma mRNA expression in pulmonary lymphocytes in equine heaves. Vet Immunol Immunopathol 2004;97: 1. Introduction 87–96. One trend that is coming to light is the fact that 5. Kolm-Stark G, Wagner R. Intradermal skin testing in Ice- horses, as well as humans, dogs, and cats, commonly landic horses in Austria. Equine Vet J 2002;34:405–410. 6. Lorch G, Hillier A, Kwochka KW, et al. Comparison of im- have combination allergies (i.e., insect allergies, mediate intradermal test reactivity with serum IgE quanti- atopy, and drug and food hypersensitivities). It is, tation by use of a radioallergosorbent test and two ELISA in therefore, important to keep in mind key concepts horses with and without atopy. J Am Vet Med Assoc 2001; such as “allergic threshold” and “summation of ef- 218:1314–1322. fect” when diagnosing and treating equine allergic 7. Lorch G, Hillier A, Kwochka KW, et al. Results of intrader- mal tests in horses without atopy and horses with chronic dermatoses. That is, a successful therapeutic pro- obstructive pulmonary disease. Am J Vet Res 2001;62:389– tocol must encompass the patient’s pre-disposing/ 397. environmental influences along with treating the 8. Lorch G, Hillier A, Kwochka KW, et al. Results of intrader- secondary perpetuating factors (bacteria and mal tests in horses without atopy and horses with atopic Malassezia), all while specifically targeting the pri- dermatitis or recurrent urticaria. Am J Vet Res 2001;62: 1051–1059. mary etiology. Regardless of which combination of 9. Jose-Cunilleras E, Kohn CW, Hillier A, et al. Intradermal therapeutic options is selected for the horse, the testing in healthy horses and horses with chronic obstructive client must be educated regarding the chronicity of pulmonary disease, recurrent urticaria, or allergic dermati- equine allergies, the workload involved in multimo- tis. J Am Vet Med Assoc 2001;219:1115–1121. dal therapy, and the realistic expectations for con- 10. Lebis C, Bourdeau P, Marzin-Keller F. Intradermal skin tests in equine dermatology: a study of 83 horses. Equine trol of the condition. Vet J 2002;34:666–671. 11. Fadok VA. Update on equine allergies. J Vet Allergy Clin 2. Environmental Control Immunol 1997;5:68–76. Avoidance or reduced allergen exposure is the best 12. Scott DW, Miller WM. Skin immune system and allergic treatment for all allergic forms. Although this op- skin diseases. In: Scott DW, Miller WM, eds. Equine der- matology. Philadelphia: W.B. Saunders, 2003;436–448. tion if often impractical, it must be offered and con- 13. Wong D, Manning T. Equine skin: structure, immunologic sidered as an adjunct to systemic therapy by the function, and methods of diagnosing disease. Compend Cont owner in lieu of lifelong anti-inflammatory therapy. Educ Pract Vet 2005;27:463–473. There are many recommendations of how to reduce/ 14. Cannon A. Clinical signs of allergy, in Proceedings. 21st avoid allergen exposure. North American Veterinary Dermatology Forum 2006;59– 61. 15. White SD. Advances in equine atopic dermatitis, serologic 1. Move from the current environment, which and intradermal allergy testing. Clin Tech Equine Pract may include moving to a different part of the 2005;4:311–313. country, moving down the road, moving to a 16. Tallarico NJ, Tallarico CM. Results of intradermal allergy different barn (bank barn versus open air), or testing and treatment by hyposensitization of 64 horses with chronic obstructive pulmonary disease, urticaria, headshak- restricting indoor/outdoor activity depending ing, and/or reactive airway disease. J Vet Allergy Clin Im- on allergic reactions (put horses with mold munol 1998;6:25–35. spore and dust allergies to pasture and keep 17. Halliwell REW, McGorum BC, Irving P, et al. Local and horses with summer pasture associated al- systemic production in horses affected with chronic lergies indoors). obstructive pulmonary disease. Vet Immunol Immuno- pathol 1993;38:201–215. 2. Minimize dust exposure in the barn, which 18. Schmallenbach KH, Rahman I, Sasse HH, et al. Studies on may include switching to rubber mats and/or 1–4 pulmonary and systemic Aspergillus fumigatus-specific IgE minimum dust generating bedding, or and IgG antibodies in horses affected with chronic obstruc- switching to grass silage, hydroponic or wet tive pulmonary disease (COPD). Vet Immunol Immuno- down hay, and/or pelleted rations. pathol 1998;66:245–256. 19. Morris DO, Lindborg S. Determination of ‘irritant’ thresh- 3. Control insects in the environment by mov- old concentrations for intradermal testing with allergenic ing horses away from standing water, ma- insect extracts in normal horses. Vet Dermatol 2003;14:31– nure piles, compost, and cattle, stabling 36. before dusk until after dawn, using fly sheets 20. DeBoer DJ, Verbrugge MJ. Results of canine serum aller- or masks sprayed with permethrin repellant, gen-specific IgE determinations performed by commercial Ϯ ϫ laboratories on canine IgE-free samples and on samples from using a 32 32 per 2.5-cm grid meshing, nonallergic dogs, in Proceedings. 20th Annual North Amer- placing box fans within the stall, using time- ican Veterinary Dermatology Forum 2005;191. release insecticide sprays, or placing fly wasps in compost and manure areas and fish in ponds. a Heska Corporation, Fort Collins, CO 80525. 4. Use dietary trials to diagnose food hypersen- bGreer Laboratories, Lenoir, NC 28645. cBiomedical Laboratory, Austin, TX 78712. sitivity or intolerance. Current recommen- dSpectrum Laboratories, Tempe, AZ 85281. dations consist of a 4- to 6-wk trial using eDormosedan, Pfizer, Exton, PA 19380. novel food sources like timothy, rolled oats,

AAEP PROCEEDINGS ր Vol. 52 ր 2006 469 IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY

Table 1. Respirable Dust and Mold Spores in a Variety of Feed and Bedding

Respirable Dust A. fumigatus F. rectivirgula T. vulgaris Feed/bedding (particles ϫ 103/l) (CFU/l) (CFU/l) (CFU/l)

Good hay 63.0 (30.0) 20.1 (5.6) 3.1 (1.2) 3.3 (1.2) Silage 78% D.M. 8.8 (2.5) 11.5 (6.5) 1.7 (1.2) 2.2 (0.7) Silage Ϯ 50% D.M. 4.5 (1.9) 4.5 (4.2) 0.4 (0.2) 1.2 (0.8) Alfalfa pellets 9.5 (4.4) 2.6 (2.5) 0.1 (0.0) 0.4 (0.2) Wood 31.5 (12.9) 16.7 (2.9) 1.2 (0.7) 1.9 (1.4) Cleanbox wood shavings 6.2 (0.1) 0.04 (0.05) 0.02 (0.04) 0.15 (0.09) Good straw 11.6 (4.9) 9.5 (5.0) 0.4 (0.4) 0.8 (0.4) Flax straw 9.3 (1.8) 2.4 (0.5) 0.2 (0.2) 1.4 (0.3) Ecobed cardboard 5.7 (1.6) 0.03 (0.05) 0 (0) 0 (0.01) Rolled grains 120.3 (30.6) 10.2 (0.6) 1.8 (1.6) 1.1 (1.1) Whole grains 4.1 (0.9) 4.5 (1.5) 0.1 (0.0) 1.0 (0.1) Mollassed concentrates 2.1 (0.6) 0.8 (0.3) 0.3 (0.2) 3.0 (1.8)

Material was agitated in an air stream and particulates expressed per liter of air. Adapted from Robinson NE. Recurrent airway obstruction (heaves). In Lekeux P (ed.) Equine Respiratory Diseases. Ithaca: International Veterinary Information Service; 2001.

alfalfa, or barley if not routinely fed. Previ- ences in the dustiness and hygienic quality of peat ous alfalfa exposure through medications, bedding. treats, or hay cubes should be investigated, Another study evaluated shredded cardboard as and unnecessary supplements, vitamins, and an appropriate minimum dust bedding. Pulmo- other drugs should be discontinued. To re- nary function tests (ventilatory mechanics, arterial challenge, add one item back into feeding blood gases, airway inflammation scoring, and bron- every 7 days; exacerbation of clinical signs choalveolar cytology) were significantly different usually occurs within 24–72 h. from those recorded in poor hygienic conditions.3 5. Other allergens that owners might overlook On basis of the in vitro and in vivo results, it was include detergent for the blanket/ concluded that cardboard bedding, used in conjunc- saddle pad/leg bandages, topically applied tion with low dust forage, might be appropriate in wound ointments, sprays, and powders, and the provision of minimum dust management of regular dewormers and vitamin supple- heaves affected horses (Table 1). ments. Food allergens are another route by which clini- cians can help minimize/eliminate allergen load by In a study evaluating the positive effects of environ- avoidance alone. In a study of 22 cases of recurrent ment versus environment and anti-inflammatory or chronic urticaria in racehorses therapy, a simple change to wood shavings and a during training season, food allergy seemed to exac- pelleted diet for 2 wk from straw and hay resulted in erbate the clinical symptoms.5 Intradermal skin improvement of recurrent airway obstruction (RAO) tests with fresh allergenic food potentiated syn- in 12 horses within 3 days and continued to 7 days.1 dromic reactions in some horses, and elimination of The addition of steroids in a crossover study induced the suspect allergen brought about resolution of a more rapid reduction in airway inflammation but clinical signs such as urticaria and enteritis. In not a more rapid improvement in airway function, general, an elimination trial of high protein food which is most likely attributable to the use of pred- items, supplements, flavored medications, and any nisone (decreased bioavailability) versus pred- molasses-containing products for a minimum of 4–6 nisolone or . Overall, airway wk is worthwhile when attempting to minimize the function was best after 30 days at pasture. The patient’s allergen load. notable improvement in lung function within 3 days of an environmental modification emphasizes the 3. Topical Control need for allergen reduction as the cornerstone of When treating horses with allergies, patient fly con- treatment of RAO.1,4 trol is a mandatory part of any therapeutic regimen. An investigation of various peat-moss composites A spray containing permethrin and an insect growth revealed fungi in sphagnum peat, various levels of regulator (pyriproxyfen; Knockout L.A.,a) was effec- endotoxin pending storage conditions, and the pres- tive in treating horses with Culicoides spp. hyper- ence of thermophilic actinomycetes and Aspergillus sensitivity.6 Other recommended repellants fumigatus in few flowered peat materials.2 The include Avon Skin-So-Soft Bath Oil diluted 50:50 concentrations of inhalable dust were smaller in the with water and Skin-So-Soft Bug Guard Plus few flowered peats (C-D) than in the sphagnum IR3535 lotion with sunscreen or an aqueous DEET peats (A-B). It was concluded that there are differ- (N,N-diethyl-m-toluamide) solution at a concentra-

470 2006 ր Vol. 52 ր AAEP PROCEEDINGS IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY tion of 16.6% (a previously approved but recently actions, thus minimizing the production of interleu- discontinued equine product is Ceratexb).6–10 Ap- kin (IL)-4, IL-5, and other inflammatory mediators, plication frequency will depend on the product se- such as chemokines, and of course, the traditional lection, geographic insect distribution, season of the products of IgE mediated mast-cell degranulation. year, and severity of the patient’s condition. Shampoo therapy should not be overlooked in the 5. Allergen Specific Immunotherapy treatment of equine allergies. The simple act of Allergen specific immunotherapy (ASIT) is a useful bathing with cool water rehydrates the skin, im- non-steroidal long-term treatment alternative in proves the integrity of the epidermal barrier, results equine veterinary dermatology. It has been used to in the vasoconstriction that decreases delivery of control insect hypersensitivities, urticaria second- inflammatory mediators to the skin, helps to mini- ary to atopy, and allergen induced RAO in horses mize percutaneous absorption of allergens, and fi- with anticipated improvement in some cases as nally, with appropriate ingredient selection, early as 2 mo.13 However, a minimum of 12 mo is addresses secondary superficial infections. The se- necessary to determine ASIT’s efficacy in an allergic lection of shampoos should be based on the patient’s patient. ASIT may also be a consideration when and may include colloidal oatmeal treating allergy induced head shaking and products (shampoos, conditioners, and bath treat- laminitis.14 ments) with or without a local anesthetic (pramox- Although the mechanism of action of immunother- ine HCl) or for pruritic dermatoses, apy is not clearly defined, there are several theories sulfur/salicylic acid shampoos for horses with excess that have been proposed. scale, antimicrobial shampoos (benzoyl peroxide, chlorhexidine or ) if secondary infections 1. Induces immunoglobulin G (IgG) blocking have been identified, or a combination of one or more antibody production in secretions, serum, of the above. and tissue.15,16 Lime sulfur (LymDypc) is a very effective multi- 2. Decreases circulating IgE by stimulating T modal topical therapeutic, because it provides not regulatory cells.16 only ectoparasitic activity but also antipruritic, an- 3. Decreases the number of mast cells and/or tiseborrheic, and antimicrobial effects in all ani- mast cell response to antigen.17 mals. Although off label, it is a safe and proven treatment option that can be applied as a dip or When selecting allergens for inclusion into ASIT, spray on horses. historical correlation with the allergy test findings Topical steroids have also shown good efficacy along with likelihood of allergen exposure is key. when treating small animal patients. Unfortu- ASIT has shown mixed results for treatment of in- nately, most of these products are not labeled for use sect hypersensitivity, urticaria secondary to atopy, in equine medicine. I have used several topical and RAO ranging from 16% to 90% effica- steroid products for treatment of localized lesions. cy.10,11,13,18–23 A recent report reflected the cur- rent concensus that ϳ60–70% of atopic horses Resicortd is a mild 1% , leave-on improve with ASIT.11 Although the exact reasons conditioner in a non-irritating base. for inconsistencies in response to ASIT may be Steroid ointments or creams (Aclovatee [alclo- caused by individual response, a number of factors metasone 0.05%] or Eloconf [ 0.1%]) may contribute to the variable responses. have different potencies (mild-moderate and high, respectively). ● Lack of allergen standardization. Genesis Topical Sprayg is a 0.015% ● Selection of antigen (was it based on intradermal, spray. serologic, or both) for allergen concentrations. ● Incorporation of non-specific immunostimu- When choosing a , one must strive for lants (e.g., mycobacterial cell wall). products with minimal side effects (i.e., minimal to ● Induction of immunotherapy and maintenance no hematological and biochemical changes, suppres- protocols. sion of the adrenal axis, and local cutaneous alter- ● Administration of allergen (dose and route; ations [, alopecia, comedone formation, and i.e., SC or intradermal). secondary infections]). ● Use of post-induction aftercare. ● Lack of objective data in a controlled environ- 4. Systemic Therapy ment. Along with the traditional immunoglobulin E (IgE)- mediated allergic reactions, it seems that the Further studies with the standards set forth by the T-helper-1/T-helper-2 paradigm, along with all its Canine Atopic Task Force24 need to be performed to alterations, exists in some form in the lung reliably assess the efficacy of this treatment modal- of horses with RAO.10–12 Similar to other domestic ity in horses. species, our focus on treatment of allergies should be However, based on the positive responses, mini- directed at reestablishing the balance of T-cell inter- mal side effects (local reaction), decreased

AAEP PROCEEDINGS ր Vol. 52 ր 2006 471 IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY dosing frequency/workload for the owner, and cost times complemented by other mechanisms of action efficacy (weight independent dosing), ASIT in horses including anti-serotonin/serotonin re-uptake inhibi- is a viable therapeutic modality for long-term con- tion. Exact dosing and recent pharmacokinetic trol of insect hypersensitivity, recurrent urticaria/ studies are lacking in the horse.29–32 The following pruritus, and RAO. Even in competitive trial and are the antihistamines and TCAs that are being show horses where concerns about the use of medi- prescribed to horses (in my personal order of prefer- cation and drug testing arise, hyposensitization pro- ence).33 vides an alternative treatment modality that may allow the horse to return to performance standards 1. hydrochloride or pamoate (0.5– and not compromise the rider’s ethics. 1.0 mg/kg, q 8 h). 2. hydrochloride (0.5–0.75 mg/kg, q 5. Polyunsaturated N-3 and N-6 Fatty Acids 12 h). Most mammalian cell membranes incorporate poly- 3. (1–2 mg/kg, q 12 h). unsaturated N-3 and N-6 fatty acids (PUFAs), and 4. Chlorpheniramine (0.25 mg/kg, q 12 h). they are thought to create a shift in the production of 5. (0.75–1 mg/kg, q 12 h). pro-inflammatory mediators to non- or anti-inflam- 6. Pyrilamine maleate (1 mg/kg, q 12 h). matory mediators in the arachidonic acid cascade. Other possible mechanisms by which PUFAs exert Similar to humans and other domestic species, there their positive clinical benefit in atopic dermatitis are is tremendous variation in response to antihista- still under investigation. Fatty acid supplements mines/TCAs. It is sometimes necessary to try sev- have shown variable reported responses in hors- eral different classes of antihistamines at 2-wk es.25–28 The difference in results is most likely at- intervals before finding the most effective option. tributable to the variability of the research Despite the paucity of synergism between antihista- parameters. mines/TCAs and other anti-inflammatory therapies in the horse, it is worthwhile to combine therapies 1. Source and dose of fatty acid being given and based on the numerous positive studies in dogs and in food (linseed oil and flaxseed meal versus cats. Although antihistamines and TCAs have oil and marine fish oils). fewer reported side effects (light sedation and occa- 2. Type of allergic reaction being evaluated (in- sional personality changes) than corticosteroids, one sect allergy versus atopy versus other). must always keep in mind the anticholinergic prop- 3. Parameters being evaluated (intradermal test erties of these medications, particularly in patients reaction versus circulating plasma fatty acid or with glaucoma, gastrointestinal atony, cardiac ar- inflammatory mediator concentrations). rhythmias, or urinary retention problems. Lastly, 4. Length of the study. advise owners to contact show authorities regarding 5. Number of horses in the study. drug restrictions/withdrawals at least 14 days be- 6. Study design (randomized double-blind pla- fore the event. cebo controlled Ϯ crossover and 6-wk washout). 8. Phosphodiesterase Inhibitors 7. Geographic location of the studies (Florida, Pentoxifylline (PTX) is a synthetic xanthine deriva- Oregon, United Kingdom, and Canada). tive related to caffeine and theophylline. Its phos- phodiesterase inhibition imparts three major Currently, it is difficult to make any conclusions on therapeutic benefits.34–42 the efficacy of the essential fatty acids based on current equine studies. Our knowledge of clinical 1. It improves wound healing and connective- benefits of PUFAs in recent canine atopic dermatitis tissue disorders by increasing fibroblast col- studies along with the lack of significant adverse lagenases, decreasing fibroblast , reactions (mainly diarrhea) would prescribe its use fibroblast fibronectin, and fibroblast glycos- in equine dermatology as adjunct to any long-term aminoglycans, and decreasing response to anti-inflammatory protocol. Typically, improve- tumour necrosis factor (TNF)-alpha. ment in pruritus and/or skin condition should be 2. Rheologic agents decrease platelet aggrega- noted within 2–8 wk after initiating therapy.10 tion and adhesion, increase red cell deform- A variety of PUFAs exist on the veterinary market ability, decrease vasoconstriction, increase and are typically administered at their labeled dose plasminogen activator, plasmin, and anti- h (Derm 100s; 1 capsule per 100 lbs divided thrombin III, and decrease fibrinogen, alpha2 twice daily). antiplasmin, alpha1 antitrypsin, and alpha2 macroglobulin modulating effects. 7. Antihistamines and Tricyclic 3. Immunomodulators inhibit T- and B-cell ac- Antihistamines and tricyclic antidepressants (TCA) tivation and proliferation, increase leukocyte provide a non-steroidal alternative for long-term deformability and chemotaxis, decrease leu- control of allergic reactions in horses. The H1-re- kocyte adhesion and aggregation, decrease ceptor antagonist activity of these drugs is some- neutrophil superoxide release and neutrophil

472 2006 ր Vol. 52 ր AAEP PROCEEDINGS IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY degranulation, decrease monocyte TNF-al- dose inhalers (MDI) may help minimize concerns pha production, leukocyte response to TNF- regarding glucocorticoid side effects while dispers- alpha, lymphotoxin, and interferon-gamma, ing maximal concentration of drug at the effector decrease production and leukocyte response sites.55,56 Masks have been designed for use with to IL-1 and IL-12, increased production of MDIsi to improve drug delivery. Beclomethasone IL-10 and PGE2, and decrease natural killer diproprionate and fluticasone propionate are both cell activity. efficacious and well tolerated by horses, but some- times these MDI steroids have a delayed response of By one or many of the mechanisms above, PTX po- Ն4 days; this necessitates combining them with tentiates the effectiveness of many medications in- faster acting drugs such as bronchodilators and sys- cluding steroids (steroid sparing effect).43–48 For temic corticosteroids. As well, MDI steroids have this reason as well as the fact that PTX’s rheologic few residual effects after treatment is activity potentially minimizes the risk of laminitis,49 discontinued.56 I tend to use pentoxifylline (8–10 mg/kg, q 12–24 h)10,50 in conjunction with steroids. This provides a 10. Cyclosporine non-steroidal alternative with minimal side effects Cyclosporine has been used in the management of (hyperexcitability and sweats) for the purpose of human, feline, and canine atopic dermatitis. How- tapering or eliminating the need for glucocorticoids ever, the lack of pharmacokinetic data in horses and in immune-mediated and allergic dermatoses. moreover, the cost of the medication limits its use in This medication should not be used in conjunction equine medicine at this time. with anticoagulants or in patients with hemorrhagic disorders. 11. Other Treatment Options j 9. Corticosteroids Methylsulfonylmethane (MSM ) can be used in con- junction with other anti-inflammatory therapies for Corticosteroids have long been a standard therapy its antioxidant properties. Controlled studies are for allergies in the horse. Corticosteroids work pri- lacking regarding its efficacy in equine allergies; marily by repression and inhibition of nuclear however, because of the absence of significant side factor kappa B, which directly or indirectly prevents effects, I continue to use the product initially at the production of cytokines, chemokines, cell adhe- 10–12 gm/500 kg q 12 h and then taper to a once sion molecules, complement factors, and prostaglan- daily dose. din and leukotriene synthesis involved in the Some of the earlier and more recent research of allergic response. Unfortunately, aggressive use of anti-inflammatory modalities is focused on receptor corticosteroids in horses may cause various adverse antagonists (platelet-activating factor receptor an- effects, including steroid hepatopathy, laminitis, 57 51–53 tagonist and eotaxin receptor [CCR3] antago- and iatrogenic hyperadrenocorticism. Individ- nists58), protein kinase-C inhibitors and its ual sensitivity to glucocorticoids may be directly re- subsequent effects on eosinophils,59 and monoclonal ␤ lated to Type 1:Type 2 11- -hydroxysteroid antibodies directed against cytokines (anti-IL-4 dehydrogenase ratio. Judicious use, appropriate monoclonal antibody [pascolizumab]60). With each amounts, and intervals are key to minimizing ad- study, we hope to learn more about the pathogenesis verse reactions. The following are the two most of allergies and ultimately, find the key to turn off commonly used glucocorticoids used for the short- the allergic response with minimal side effects and term treatment of equine allergies. cost.

1. Prednisolone: syrup compounded or tablets References and Footnotes at 0.5–1.5 mg/kg/day for 7–14 days and then 1. Jackson CA, Berney C, Jefcoat AM, et al. Environment and tapering to 0.2–0.5 mg/kg, q 48 h over 2–5 wk interactions in the treatment of recurrent airway for maintenance. If cost is an issue, pred- obstruction (heaves). Equine Vet J 2000;32:432–43 8. nisone may be substituted for prednisolone; 2. Airaksinen S, Heiskanen ML, Heinonen-Tanski H, et al. the latter has been shown to have greater Variety in dustiness and hygiene quality of peat bedding. Ann 54 Agric Environ Med 2005;12:53–59. bioavailability in horses. 3. Kirschvink N, Di Silvestro F, I, et al. The use of card- 2. Dexamethasone: powder or tablets. In- board bedding material as part of an environmental control jectable dexamethasone solution given orally regime for heaves-affected horses: in vitro assessment of is 60–70% bioavailable compared with the IV dust and aeroallergen concentration and in vivo route.11 The initial loading oral or IV pulse effects on lung function. Vet J 2002;163:319–325. 4. Leguillette R. Recurrent airway obstructionϪheaves. dose is 0.05–0.1 mg/kg daily for 3–7 days and Vet Clin North Am [Equine Pract] 2003;19:63–86. then tapering to 0.01–0.02 mg/kg every 5. Volland-Francqueville M, Sabbah A. Recurrent or chronic 48–72 h for maintenance. This regime is urticaria in Thoroughbred racehorses: clinical observations. particularly helpful in more refractory cases. Allerg Immunol () 2004;36:9–12. 6. Bourdeau PJ, Beis C, Chouilly C, et al. Evaluation of per- methrin and pyriproxyfen containing spray in the treatment Lastly, when addressing allergy induced RAO, the of sweet itch in 25 horses, in Proceedings. 15th Annual use of locally dispersed steroids through metered- Member’s Meeting of the American Academy of Veterinary

AAEP PROCEEDINGS ր Vol. 52 ր 2006 473 IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY

Dermatology/American College of Veterinary Dermatology 29. Foster AP, McKelvie J, Cunningham FM. Inhibition of an- 1999;13–14. tigen-induced cutaneous responses of ponies with insect hy- 7. Fadok VA. Update on equine allergies. J Vet Allergy Clin persensitivity by the -1 receptor antagonist Immunol 1997;85:68–76. chlorpheniramine. Vet Rec 1998;143:189–193. 8. Gortel K. Equine parasitic hypersensitivity: a review. 30. Wasfi IA, Abdel Hadi AA, Elghazali M, et al. Comparative Equine Pract 1998;20:14–16. pharmacokinetics of diphenhydramine in camels and horses 9. Rees C. Diagnosing and managing equine pruritus: insect after intravenous administration. Vet Res Commun 2003; hypersensitivity. Compend Cont Educ Pract Vet 2005;27: 27:463–473. 629–636. 31. Torneke K, Ingvast-Larsson C, Pettersson K, et al. Pharma- 10. Scott DW, Miller WM. Skin immune system and allergic cokinetics and pharmacodynamics of clemastine in healthy skin diseases. In: Scott DW, Miller WM, eds. Equine der- horses. J Vet Pharmacol Ther 2003;26:151–157. matology. Philadelphia: W.B. Saunders, 2003;436–448. 32. Manohar M, Goetz TE, Humphrey S, et al. H1-receptor 11. White SD. Advances in equine atopic dermatitis, serologic antagonist, tripelennamine, does not affect arterial hypox- and intradermal allergy testing. Clin Tech Equine Pract emia in exercising Thoroughbreds. J Appl Physiol 2002;92: 2005;4:311–313. 1515–1523. 12. Cordeau ME, Joubert P, Dewachi O, et al. IL-4, IL-5 and 33. Yu AA. Equine urticaria: a diagnostic dilemma. Com- IFN-gamma mRNA expression in pulmonary lymphocytes in pend Cont Educ Pract Vet 2000;22:277–280. equine heaves. Vet Immunol Immunopathol 2004;97:87–96. 34. Schmidt-Choudhury A, Furuta GT, Lavigne JA, et al. The 13. Rees CA. Response to immunotherapy in six related horses regulation of tumor necrosis factor-alpha production in mu- with urticaria secondary to atopy. J Am Vet Med Assoc rine mast cells: pentoxifylline or dexamethasone inhibits 2001;218:753–755. IgE-dependent production of TNF-alpha by distinct mecha- 14. Wagner IP, Rees CA, Dunstan RW, et al. Evaluation of nisms. Cell Immunol 1996;171:140–146. systemic immunologic hyperreactivity after intradermal test- 35. Rickards KJ, Page CP, Lees P, et al. In vitro and ex vivo ing in horses with chronic laminitis. Am J Vet Res 2003;64: effects of the phosphodiesterase 4 inhibitor, rolipram, on 279–283. thromboxane production in equine blood. J Vet Pharmacol 15. Greenberger PA. Immunotherapy of IgE-mediated disor- Ther 2003;26:123–130. ders. Immunol Allergy Clin North Am 1992;12:125–144. 36. Sykes BW, Furr MO. Equine endotoxaemiaϪa state-of-the- 16. Akdis M, Blaser K, Akdis CA. T regulatory cells in allergy: art review of therapy. Aust Vet J 2005;83:45–50. novel concepts in the pathogenesis, prevention, and treat- 37. Barton MH, Ferguson D, Davis PJ, et al. The effects of ment of allergic diseases. J Allergy Clin Immunol 2005: pentoxifylline infusion on plasma 6-keto-prostaglandin F1 961–968. alpha and ex vivo endotoxin-induced tumour necrosis factor 17. Durham SR, Varney VA, Gaga M, et al. Grass pollen im- activity in horses. J Vet Pharmacol Ther 1997;20:487–492. munotherapy decreases the number of mast cells in the skin. 38. Barton MH, Moore JN, Norton N. Effects of pentoxifylline Clin Exp Allergy 1999;29:1490–1496. infusion on response of horses to in vivo challenge exposure 18. Delger JM. Intradermal testing and immunotherapy in with endotoxin. Am J Vet Res 1997;58:1300–1307. horses. Vet Med 1997;92:635–639. 39. Weiss DJ, Richwagen K, Evanson OA. Effects of hematocrit 19. Anderson GS, Belton P, Jahren E, et al. Immunotherapy and erythrocyte deformability on pulmonary vascular pres- trial for horses in British Columbia with Culicoides (Diptera: sures in perfused pony lungs. Am J Vet Res 1996;57:346– Ceratopogonidae) hypersensitivity. J Med Entomol 1996; 350. 33:458–466. 40. Chilcoat CD, Rowlingson KA, Jones SL. The effects of cAMP 20. Barbet J, Bevier D, Greiner EC. Specific immunotherapy in modulation upon the adhesion and respiratory burst activity the treatment of Culicoides hypersensitive horses: a double- blind study. Equine Vet J 1990;22:232–235. of immune complex-stimulated equine neutrophils. Vet Im- 21. Rosenkrantz WS, Griffin CE, Esch RE, et al. Response in munol Immunopathol 2002;88:65–77. horses to intradermal challenge of insects and environmental 41. Zabel P, Entzian P, Dalhoff K, et al. Pentoxifylline in treat- allergens with specific immunotherapy, in Proceedings. 3rd ment of . Am J Respir Crit Care Med 1997;155: World Congress of Veterinary Dermatology 1996;191–200. 1665–1669. 22. Tallarico NJ, Tallarico CM. Results of intradermal allergy 42. Leguillette R, Desevaux C, Lavoie JP. Effects of pentoxifyl- testing and treatment by hyposensitization of 64 horses with line on pulmonary function and results of cytologic examina- chronic obstructive pulmonary disease, urticaria, headshak- tion of bronchoalveolar lavage fluid in horses with recurrent ing, and/or reactive airway disease. Vet Allergy Clin Immu- airway obstruction. Am J Vet Res 2002;63:459–463. nol 1998;6:25–35. 43. Briggs WA, Eustace J, Mathew S, et al. Pentoxifylline po- 23. Wong D, Manning T. Equine skin: structure, immunologic tentiates in vitro lymphocyte suppression by glucocorticoids function, and methods of diagnosing disease. Compend Cont and immunosuppressive drugs. J Clin Pharmacol 1998;38: Educ Pract Vet 2005;27:463–473. 561–566. 24. Griffin CE, Hillier A. The ACVD task force on canine atopic 44. Entzian P, Zahringer U, Schlaak M, et al. Comparative dermatitis (XXIV): allergen-specific immunotherapy. Vet study on effects of pentoxifylline, prednisolone and Immunol Immunopathol 2001;81:363–383. in experimental alveolitis. Int J Immunopathol Pharmacol 25. O’Neill W, McKee S, Clarke AF. Flaxseed (Linum usitatis- 1998;20:723–735. simum) supplementation associated with reduced skin test 45. Funk JO, Ernst M, Schonharting MM, et al. Pentoxifylline lesional area in horses with Culicoides hypersensitivity. exerts synergistic immunomodulatory effects in combination Can J Vet Res 2002;66:272–277. with dexamethasone or cyclosporin A. Int J Immunopathol 26. Friberg CA, Logas D. Treatment of Culicoides hypersensi- Pharmacol 1995;17:1007–1016. tive horses with high-dose n-3 fatty acids: a double-blinded 46. Baskett A, Barton MH, Norton N, et al. Effect of pentoxi- cross over study. Vet Dermatol 1999;10:117–122. fylline, flunixin meglumine, and their combination on a 27. Craig JM, Lloyd DH, Jones RD. A double-blind placebo- model of endotoxemia in horses. Am J Vet Res 1997;58: controlled trial of an evening primrose and fish oil combina- 1291–1299. tion vs. hydrogenated coconut oil in the management of 47. Kasahara E, Yamagishi N, Tanaka M, et al. A child with recurrent seasonal pruritus in horses. Vet Dermatol 1997; simple of the colon effectively treated with the combi- 8:177–182. nation of prednisolone, , and pentoxifylline. J 28. Hall JA, Van Saun RJ, Tornquist SJ, et al. Effect of type of Gastroenterol 2002;37:745–749. dietary polyunsaturated fatty acid supplement (corn oil or 48. Kiku Y, Matsuzawa H, Ohtsuka H, et al. Effects of chlor- fish oil) on immune responses in healthy horses. J Vet Int , pentoxifylline and dexamethasone on mRNA Med 2004;18:880–886. expression of lipopolysaccharide-induced inflammatory cyto-

474 2006 ր Vol. 52 ր AAEP PROCEEDINGS IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY

kines in bovine peripheral blood mononuclear cells. J Vet 58. Benarafa C, Collins ME, Hamblin AS, et al. Role of the Med Sci 2002;64:723–726. chemokine eotaxin in the pathogenesis of equine sweet itch. 49. Ingle-Fehr JE, Baxter GM. The effect of oral Vet Rec 2002;151:691–693. and pentoxifylline on digital and laminar blood flow in 59. Greenaway EC, Sepulveda MF, Cunningham FM, et al. healthy horses. Vet Surg 1999;28:154–160. Protein kinase C (PKC) isotype profile in eosinophils from 50. Crisman MV, Wilcke JR, Correll LS, et al. Pharmacokinetic ponies with sweet itch and role in histamine-induced eosin- disposition of intravenous and oral pentoxifylline in horses. ophil activation. Vet Immunol Immunopathol 2003;96:53– J Vet Pharmacol Ther 1993;16:23–31. 63. 51. Cohen ND, Carter GK. Steroid hepatopathy in a horse with 60. Hart TK, Blackburn MN, Brigham-Burke M, et al. Preclini- glucocorticoid-induced hyperadrenocorticism. JAmVet cal efficacy and safety of pascolizumab (SB 240683): a hu- Med Assoc 1992;200:1682–1684. 52. Vandenabeele SIJ, White SD, Affolter VK, et al. Pemphigus manized anti-interleukin-4 antibody with therapeutic foliaceus in the horse: a retrospective study of 20 cases. potential in asthma. Clin Exp Immunol 2002;130:93–100. Vet Dermatol 2004;15:381–388. 53. Johnson PJ, Slight SH, Ganjam VK, et al. Glucocorticoids and laminitis in the horse. Vet Clin North Am [Equine aKnockout L.A., Virbac, Peakhurst, NSW 2210, Australia. Pract] 2002;18:219–236. bCeratex, Vet Genix, Coral Gables, FL 33134. 54. Peroni DL, Stanley S, Kollias-Baker C, et al. Prednisone per cLymDyp, DVM Pharmaceuticals, Miami, FL 33137. os is likely to have limited efficacy in horses. Equine Vet J dResicort, Virbac, Peakhurst, NSW 2210, Australia. 2002;34:283–287. eAclovate, GlaxoSmithKline Consumer Healthcare LP, Pitts- 55. Leguillette R. Recurrent airway obstruction—heaves. burgh, PA 15230. Vet Clin North Am [Equine Pract] 2003;19:63–86. fElocon, Schering Corporation, Kenilworth, NJ 07033. 56. Lavoie JP. Heaves. In: Bertone J, Brown CM, eds. The 5 gGenesis Topical Spray, Virbac AH, Inc., Fort Worth, TX 76137. minute veterinary consult—equine. Baltimore: Lippincott, hDerm Caps 100s, DVM Pharmaceuticals, Miami, FL 33137. Williams & Wilkins, 2002;478–479. iEquine Aeromask, Trudell Medical International, London, ON, 57. Foster AP, Lees P, Cunningham FM. Actions of PAF recep- Canada N5V 5G4. tor antagonists in horses with the allergic skin disease sweet jMSM, Vita-Flex Nutrition Co, Council Bluffs, IA 51501. itch. Inflamm Res 1995;44:412–417.

II. Nodules, Lumps, and Bumps

Nodules—Infectious to regress during the first month of treatment, and treatment should be continued for at least 1 mo Stephen D. White, DVM, Diplomate ACVD beyond the complete resolution of all cutaneous nod- 1. Infectious ules and healing of any ulcerated lesions. Discon- tinuing therapy prematurely will invariably result A serious yeast-caused disease is sporotrichosis in an unnecessary relapse of the disease. During (Sporothrix schenkii), which presents as a nodular to ulcerative lymphatic cording disease (Fig. 1). Diag- treatment, the horse should be closely observed for nosis is made when the organism is detected on any evidence of iodide toxicity (iodism), which in- histopathology, immunofluorescent antibody testing cludes excess scaling and alopecia, a serous ocular or on affected tissues, impression smears, and/or cul- nasal discharge, excess salivation, anorexia, depres- ture.1 This is a , and therefore, care should sion, coughing, nervousness, or cardiovascular ab- be taken in handling suspected samples. Success- normalities. Should any of these signs develop, the ful therapy with a number of different systemic io- treatment should be discontinued for 1 wk and re- dine preparations (NaI or KI) has been reported. sumed at three-quarters of the dosage at which the The organic iodides have proven to be superior in iodism was noted. In most instances, the treat- 2 efficacy to the inorganic iodides in the treatment of ment is subsequently well tolerated. Although equine sporotrichosis, and ethylene diamine dihy- both itraconazole and terbinafine have been shown droiodide (organic iodide powdera or EDDI 20 Gr. to be effective in vitro against the organism isolated Dextrose baseb) is the drug of choice. This product from a horse, the author is unaware of any clinical is in the form of a feed additive. It can be mixed reports in this species.3 with a small amount of grain and administered at a Habronemiasis (summer sore) is a granulomatous dosage of 1–2 mg/kg of the active ingredient once or disease caused by the deposition of Habronema ma- twice daily for the first week. The dosage is then jus, Habronema muscae,orDraschia megastoma reduced to 0.5–1.0 mg/kg once daily for the remain- larvae by flies at the site of wounds or natural body der of the treatment. In general, lesions will begin moisture (sheath or eyes).4,5 Diagnosis is based on

AAEP PROCEEDINGS ր Vol. 52 ր 2006 475 IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY been shown to be effective and is considered the treatment of choice by many clinicians. Moxidect- inc (0.4 mg/kg orally) may also be used.5 Systemic (prednisolone administered at 1 mg/kg once daily for 10–14 days and then tapered over a 2-wk period) or intralesional/topical corticosteroids often are also used because of the hypersensitivity reaction nature of the disease process. In severe cases, surgical removal or debulking of the lesion should be consid- ered.5 It should be noted that the author and oth- ers have seen this disease in horses that were routinely given ivermectin as part of their deworm- ing program.5 Corynebacterium pseudotuberculosis infections are usually present as solitary or multiple or nodules with many draining tracks that progress to diffuse cellulites. When this process affects the pectoral region, it is often termed “pigeon fever” in the United States. Some observations about this type of deep Corynebacterium infection are that it may occur where caseous lymphadenitis is common in sheep, although proximity to sheep is not a re- quirement, and that it may be seen seasonally when insect population and activity are maximal. Insect vectors seem probable, especially stable, horn, and 6 Fig. 1. Sporotrichosis causing multiple ulcers and distal limb house flies. The draining nodules or abscesses are . especially common in the pectoral region (Fig. 3), and occasionally, they affect the face, neck, , groin, and limbs. They begin deep and enlarge, often with much edema; they rupture in 1–4 wk and clinical signs, history, and presence of calcified con- discharge viscid, creamy purulent exudates, which cretions (sulfur granules), and it is confirmed by is a major source of contamination. Abscesses most biopsy. Arabians, gray horses, and horses with a often rupture externally. Treatment depends on lo- dilute haircoat are over-represented. The medial cation. For example, if the is in the axilla canthus of the eye, male genitalia, third eyelid, and and painful on movement and/or preventing locomo- distal extremities are the most common parts of the 4 tion, establishment of drainage is very important, body affected (Fig. 2). Treatment in the past has and antibiotics are indicated. Antibiotics most been either corticosteroids or organophosphates, commonly used are procaine penicillin (20,000–50,000 topically or systemic; ivermectin (0.3 mg/kg) has IU/kg/day) with rifampin (3–5 mg/kg, PO); alterna- tively, trimethoprim sulfa (TMS; 30 mg/kg, q 12 h) may be used.7,8 Treating with TMS and rifampin concurrently may lead to a greater incidence of colitis and is to be avoided. If the decision is made to use antibiotics but drainage cannot be easily established

Fig. 2. Swelling and ulceration caused by habronemiasis of the Fig. 3. Corynebacterium pseudotuberculosisϪcaused abscesses penile sheath. draining on the ventrum of a horse.

476 2006 ր Vol. 52 ր AAEP PROCEEDINGS IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY (for example, an axillary abscess where the owner is unwilling to allow the veterinarian to use a trocar and drain), the antibiotics must be used for a minimum of 1 mo. If the abscess is solitary and not causing pain or fever, antibiotics are usually not necessary, but bringing the abscess to a head with hot packs or heat- inducing agents (ichthammol) is important. After any abscess has drained, gentle cleaning with tamed iodines or chlorhexidine is indicated.

2. Neoplasms (mast cell tumors) occurs in horses 1–18 yr of age (mean ϭ 9 yr), and there is no breed predilection.9,10 A predilection for males has been proposed but is not always substantiated. There is one report in a .11 In addition, multiple mast cell tumors resembling of humans may occur in newborn foals; these sponta- neously appear and regress. Equine mastocytosis is usually solitary and occurs most commonly on the Fig. 4. Melanocytoma on a young horse. (Courtesy of Dr. J. head and trunk. Lesions are 0.5–20.0 cm in diam- Traub-Dargatz.) eter, well to poorly circumscribed, firm to fluctuant, dermal or SC, and may or may not be alopecic, ulcerated, and hyperpigmented. Lesions on the legs tend to be very firm and immovable. tumor cells, either round or dendritic, with no mito- Histology may vary from sheets of mast cells with ses. (If there are multiple, confluent dermal mela- few eosinophils (presumably early lesions) to those nomas, this is referred to as dermal melanomatosis). showing both the sheets of mast cells with numerous Eighty percent of these tumors are in horses Ͼ6yrof eosinophils and collagen degranulation. Ultra- age12 or between 5 and 15 yr,13 and it is much more structural features are similar to those noted in common in grey horses. Most of these tumors oc- mast cell tumors of other species. Clinically, most curred in typical locations. Of 14 cases available mast cell tumors in horses do not recur after being for follow-up in one study,12 8 had malignant behav- excised (22 of 25 in one study). The author knows ior as shown by metastases. of one anecdotal case of metastasis from a tumor on In another study,14 the clinical and pathological the muzzle to regional lymph nodes; the tumor and characteristics of cutaneous occurring in the nodes were removed, and the horse was clini- 83 Camargue-type gray-skinned horses showed that cally sound 3 yr later. There is some debate as to the tumors occurred most frequently underneath the whether equine mast cell tumors are benign neopla- tail (93.9%) and at high rates in the perianal region sias or focal dysplasias of mast cells. (43.0%), the lips (33.0%), and the eyelids (24.0%) but Melanocytic skin tumors of horses traditionally rarely in the (3.8%). Microscopic examination have been described in aging grey horses and on the indicated that these tumors were composed mostly of ventral tail, perineum, external genitalia, lip, udder, and numerous melanophages and that periocular, and regions. They have these cells manifested a remarkable cellular atypia. been the subject of several classification schemes in Early stages of the tumors occurred in close associa- attempt to correlate histopathologic appearance tion with apocrine sweat glands but not at the dermal- with clinical behavior (i.e., is it benign or malig- epidermal junction. nant?). One study distinguished three basic types A clinical study was conducted on 296 gray of melanocytic skin tumors.12 horses of the Lipizzane breed.15 Of the 296 Melanocytic nevi (melanocytoma) occurs in the horses, dermal melanomas were present in 148 superficial or at the epidermal-dermal junc- horses (50%), 68 of which were Ͼ15 yr of age; 51 of tion, and it frequently has epithelial involvement these were bearing. In 75.6% of cases, with nests of relatively large, mildly to moderately melanotic tumors were detected underneath the pleomorphic cells showing variable cytoplasmic pig- tail. None of the affected individuals suffered mentation and occasional mitoses (Fig. 4). More any severe clinical effect or were handicapped in than 70% of these occur in horses Ͻ6 yr of age and performance. Seltenhammer et al.15 concluded may occur in horses of any color (not just grey). that in contrast to melanomas in solid colored Most of these tumors occurred in atypical locations. horses characterized by early metastases, melano- Of 28 melanocytic nevi, only one became invasive, mas in grey horses showed less malignancy. Af- and the rest exhibited benign behavior. fected individuals often had encapsulated nodules Dermal melanomas are found in the deep dermis or structures similar to human blue nevi. Prob- and are composed of small homogeneous, indistinct ably, this finding at least partially reflects confu-

AAEP PROCEEDINGS ր Vol. 52 ր 2006 477 IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY sion in terminology between true malignant 17. Goetz TE, Ogilvie GK, Keegan KG, et al. for melanomas and dermal melanomas. treatment of melanomas in three horses. J Am Vet Med Assoc 1990;196:449–452. Anaplastic malignant melanomas were composed 18. Bowers JR, Huntington PJ, Slocombe RF. Efficacy of cime- of sheets of extremely pleomorphic epithelioid cells tidine for therapy of skin tumours of horsesϪ10 cases. Aust with poor pigmentation and many mitoses. These Equine Vet 1994;12:30–32. are usually seen in horses Ͼ20 yr of age and in a horses of any color. Neogen Corporation, Lexington, KY 40511. bEDDI 20 Gr. Dextrose base, Vedco Inc., St. Joseph, MO 64507. In regard to treatment, one study reported good cQuest® Equine Gel, Fort Dodge Animal Health, Overland success with excising dermal melanomatosis from Park, KS 66225-5945. the perineal, perianal, perirectal, or ventral tail regions.16 In a study of three horses, cimetidine Sarcoids (2.5 mg/kg,q8h,PO)wasshown to decrease the number and size of melanomas tumor growth.17 Anthony A. Yu, DVM, MS, Diplomate ACVD However, a more recent study of 10 horses found that cimetidine had no consistent effects on either 1. Introduction the number of tumors or tumor surface area over Sarcoids are one of the most common causes of lo- the 16-wk treatment at a dose of 5mg/kg, q 12 h, PO.18 cally aggressive, non-metastatic fibroblastic nodular neoplastic lesions in horses, and they account for 35–90% of dermatological neoplasms.1–4 References and Footnotes 1. Irizarry-Rovira AR, Kaufman L, Christian JA, et al. Diag- 2. Proposed Viral Etiology nosis of sporotrichosis in a donkey using direct fluorescein- labeled antibody testing. J Vet Diag Invest 2000;12:180– (animal and human ) infect 183. epithelial cells and cause hyperproliferation, , 2. Rosser EJ Jr. Sporotrichosis. In: Robinson NE, ed. Cur- , or condylomas. rent therapy in equine medicine, 5th ed. St. Louis: W.B. (BPV) is currently categorized into six subtypes and Saunders, 2003;213–214. two groups (A or B). Subgroup A transforms fibro- 3. Kohler LM, Monteiro PC, Hahn RC, et al. In vitro suscep- tibilities of isolates of to itraconazole blast and epithelial cells, whereas subgroup B trans- and terbinafine. J Clin Microbiol 2004;42:4319–4320. forms epithelial cells only. It is believed that BPV 4. Pusterla N, Watson JL, Wilson WD, et al. Cutaneous and types 1 and 2 (subgroup A) are associated with the ocular habronemiasis in horses: 63 cases (1988– genesis of sarcoid disease. Polymerase chain reac- 2002). J Am Vet Med Assoc 2003;222:978–982. tion methods have been able to detect viral DNA and 5. Rees CA, Craig TM. Equine cutaneous habronemiasis. In: Robinson NE, ed. Current therapy in equine medicine, RNA from most sarcoids and recently, expression of 5th ed. Philadelphia: W.B. Saunders, 2003;195–197. the major transforming oncoprotein, E5, of BPV 6. Spier SJ, Leutenegger CM, Carroll SP, et al. Use of a real- types 1 and 2. BPV types 1 and 2 do not seem to time polymerase chain reaction-based fluorogenic 5Ј nuclease produce infectious virions but rather persistence assay to evaluate insect vectors of Corynebacterium pseudo- and disease pathogenesis by downregulating major tuberculosis infections in horses. Am J Vet Res 2004;65: 5,6 829–834. histocompatibility complex (MHC) class I expression. 7. Farstvedt EG, Hendrickson DA, Dickenson CE, et al. Treat- ment of suppurative facial and caused 3. Signalment by Corynebacterium pseudotuberculosis in two horses. JAm Sarcoids are more often noted in donkeys and mules Vet Med Assoc 2004;224:1139–1142. 8. Aleman M, Spier SJ, Wilson WD, et al. Corynebacterium than horses. Most affected individuals are geld- pseudotuberculosis infection in horses: 538 cases ings, and the age of onset is between 1 and 7 yr. (1982–1993). J Am Vet Med Assoc 1996;209:804–809. Thoroughbreds, , and those horses that 9. McEntee MF. Equine cutaneous : morphol- often work cattle, such as Appaloosas, Arabians, and ogy, biological behavior and evolution of the lesion. J Comp Pathol 1991;104:171–178. Quarter Horses, seem predisposed to sarcoid forma- 10. Whitler WA, Schmotzer WB, Huber MJ, et al. Equine mast tion. Standardbreds seem unlikely to develop sar- cell tumor. Equine Pract 1994;16:16–21. coids, possibly because of a decreased expression of 11. Kay G, Noursaid I, El Hamidi M, et al. Grade III mastocy- the MHC class II antigen W13 ELA alleles; however, toma in a donkey. Vet Rec 2003;152:266–267. the aforementioned breeds tend to have an in- 12. Valentine BA. Equine melanocytic tumors: a retrospective 1 study of 53 horses (1988–1991). J Vet Int Med 1998;9:291–297. creased expression. 13. Fleury C, Berard F, Leblond A, et al. The study of cutaneous melanomas in Camargue-type gray-skinned horses (2): ep- 4. Clinical Findings idemiological survey. Pigment Cell Res 2000;13:47–51. Multiple lesions are noted in 14–84% of affected 14. Fleury C, Berard F, Balme B, et al. The study of cutaneous individuals (Fig. 1). Sarcoids tend to occur in areas melanomas in Camargue-type gray-skinned horses (1): clin- ical-pathological characterization. Pigment Cell Res 2000; of previous trauma or irritation by insects or tack, 13:39–46. including the chest, legs, girth, and base of the ears 15. Seltenhammer MH, Simhofer H, Scherzer S, et al. Equine along with areas of thin skin such as the periocular, melanoma in a population of 296 grey Lipizzaner horses. muzzle, and ventral abdomen (Fig. 2). Geographi- Equine Vet J 2003;35:153–157. 16. Rowe EL, Sullins KE. Excision as treatment of dermal mel- cal variation seems to result in differing distribution anomatosis in horses: 11 cases (1994–2000). JAmVet (e.g., the trunk in the United Kingdom and Switzer- Med Assoc 2004;225:94–96. land) potentially associated with feeding patterns of

478 2006 ր Vol. 52 ր AAEP PROCEEDINGS IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY

Fig. 1. Equine fibroblastic sarcoids in the groin, an area where there had previously been trauma, is a common finding.

different flies and therefore, transmission of the vi- rus to different sites.1 The fly vector transmission hypothesis is also supported by the lack of equine sarcoids in Norway, a country without biting insects. Fig. 2. Multiple occult sarcoids in the groin region of a . 5. Sarcoid Types There are multiple publications with various classi- fications of equine sarcoids. Recently, a classifica- ● Type AϪindividual or lobulated congregations 7 tion has been put forth by Knottenbelt, and a brief of spherical SC masses. summary follows. ● Type BϪprecludes independent movement of the overlying skin. Occult (Superficial) Type ● Nodular, verrucous, and flat sarcoids cause lit- tle discomfort (unless canthus of the eye). ● Presents alopecia, scaling, and skin ● Trauma may stimulate flat/verrucous/nodular thickening. sarcoids to become fibroblastic. ● Presents sarcoids that are flat, annular, slightly thickened, scaly, hyperkeratotic, and Fibroblastic Form hyperpigmented. ● Affects neck, face, peri-oral, sheath, medial ● Presents fleshy fibrovascular appearance. thigh, and shoulder. ● Often closely resembles granulation tissue/ proud flesh. Verrucous Form ● Presents rapid growth along with ulceration, , and interference with function. ● Presents sarcoids that are Ͻ6 cm and dry with ● Affects axillae, groin, legs, periocular, and pre- a horny surface and a cauliflower-like vious wound sites. appearance. ● Also affects sites of other sarcoid type subject ● Presents a prominent warty or verrucous to trauma. appearance. ● Type 1 is pedunculated. ● Affects the head, neck, axillae, and groin. ● Type 2 has a broad locally invasive base. Nodular Form Malignant/Malevolent Sarcoid

● Presents sarcoids that are entirely SC with ● Is an aggressive locally invasive form. normal overlying skin and haircoat. ● Extends widely into adjacent skin and ● Affects eyelids, groin, and sheath. subcutis.

AAEP PROCEEDINGS ր Vol. 52 ր 2006 479 IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY ● Is invasive with infiltrated lymphatic vessels. date, there is no one treatment option that has ● Has multiple cords of tumor mass. proved universally successful. Surgical excision, ● Elbow and jaw. cryosurgery, carbon dioxide LASER, radiofre- quency hyperthermia, radiotherapy, chemother- Mixed Forms apy, immunotherapy, or combinations thereof are Common with components of two or more types. summarized below.

6. Diagnosis 8. Surgical Approaches Although it has been suggested that as high as Surgical excision8,9 alone has met with 50–64% re- 50% of flat or verrucous type sarcoids that are currence within 6 mo. Thus, surgery is used more biopsied will transform into the more aggressive often to debulk the mass and improve combination fibroblastic type, a recent roundtable discussion at treatment. Typically, 0.5–1 cm margins have been the North American Veterinary Dermatology Fo- described; however, in the NAVDF roundtable, the rum (NAVDM) in 2006 among dermatologists and group felt that 3–10 cm margins were more appro- dermatopathologists from various parts of the priate in an attempt to decrease recurrence. Sur- world recommended that biopsies be taken to con- gical excision, therefore, should be performed under firm your diagnosis so that appropriate therapy general anesthesia (not local anesthesia) to perform can be pursued. If transformation is noted (typ- thorough extirpation. To close such a defect, pinch ically within 2 wk), then consider applying imi- or split thickness graft can be used. One should quimod to the affected lesion (see below) to anticipate increased healing time and excess gran- prevent transformation and provide potential res- ulation tissue. In general, a cosmetic outcome can olution. Also, the attendees at the roundtable did be achieved. not find such a high incidence of transformation; Cryotherapy8–10 has achieved up to 70% success however, it could be that the specialists are seeing with no recurrence. The procedure involves apply- a skewed population. That being said, when pos- ing probes cooled to Ϫ20–30°C directly on the sar- sible, the entire tumor should be removed. coid with 2–3 freeze/thaw cycles. Thermocouple When sampling tissue for dermatohistopathologic needles are used to monitor depth and degree of evaluation, it is advised to take large (6–8 mm) and freezing. Hyperemia, hemorrhage, swelling, and deep biopsies, because small and superficial biopsies local edema follow, resulting in damaged epithelium may read out as granulation tissue over the of a and viral particles at the site. Average healing chronic ulcerated sarcoid. Also, some sarcoids may time is 2.4 mo. The hair follicles are damaged or initially appear consistent with insect bites (eosino- destroyed, and hair regrows white or not at all. phils with reactive appearing fibrosis) and are sub- Facial nerve paralysis, septic , loss of upper sequently rebiopsied to be consistent with equine eyelid, and eviscerated globe are some of the com- sarcoid. Perhaps these cases are truly insect bites plications to discuss with the owner before embark- that later become equine sarcoids. As a general ing on this treatment modality. Regression of rule, all well differentiated spindle cell prolifera- multiple tumors (when only a select few are treated) tions appear very similar on histopathology. This has been reported inconsistently and is likely the includes granulation tissue, equine sarcoid, amela- result of a cryoimmune response to sarcoid-cell notic melanocytic tumors, nerve sheath tumors, and components. non-transmissible, non-sarcoidal well differentiated Carbon dioxide LASER11–13 cuts and evaporates fibrosarcoma. Classic equine sarcoid is fairly rec- tumor tissue with accurate dissection and excellent ognizable; however, it is not terribly dissimilar from cosmetic results. The advantages include de- the other listed differentials. The classic appear- creased to no post-operation swelling, no post-oper- ance consists of overlying epidermal hyperplasia ation pain on palpation, primary wound closure or and perpendicular arrangement of some spindle second intention healing without hypergranulation, cells with surface epithelium creating a picket fence and superior cosmesis. It has been reported that 1 pattern. Problems in diagnosis arise when there 81% of 59 horses with sarcoids treated by CO2 laser is no surface epithelium, when the lesion is trauma- were free from recurrence after 12 mo. In the same tized with overlying granulation tissue as men- study, 60% of 35 horses in which sarcoids were tioned above, or when the mass is in the deep dermis treated by cryosurgery and 64% of 14 horses in to subcutis without the overlying typical changes. which sarcoids were treated by conventional surgery In cases where the dermatohistopathology does not were sarcoid free after 12 mo. The improved suc- support the clinical diagnosis, polymerase chain re- cess rates may be caused by the extension of the action analysis for BPV may be of value. thermal-killing effects and vaporization of viral par- ticles with CO2 LASER, thus extending the margins 7. Management/Treatment and minimizing recontamination, respectively. Lesions may progress if they are handled and Regardless of the technique, animals with multiple rarely, may regress spontaneously. The general sarcoids were more predisposed to recurrence, and rule of thumb is if it is flat, leave it alone, but if it donkeys showed a significantly lower recurrence is fibroblastic, treat aggressively or refer. To rate than horses.

480 2006 ր Vol. 52 ր AAEP PROCEEDINGS IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY 9. Intralesional Approaches sarcoids resulted in regression after only two to Radiofrequency (orthovoltage) current induced hy- three electrochemotherapies in 100% of the perthermia1 involves heating sarcoids to 50°C for treated lesions. No adverse effect from the elec- 30 s (2 MHz current) with a thermoprobe every 1–3 tric pulses was observed, and no regrowth was wk. Hyperthermia is often combined with radio- observed in the 18-mo follow-up period. therapy, immunotherapy, and chemotherapy. Lim- 10. Topical Cytotoxic Approach ited reports on success of use in three cases resulted in b regression with no recurrence 7–12 mo after the last XXTerra, a caustic agent containing zinc chloride, treatment. has anecdotally had some benefit. The product also Interstitial brachytherapy4,14 using various iso- contains water and bloodroot (Sanguineria canaden- topes (e.g., permanently implanted seeds of radon- sis). XXTerra is proposed to alter the tumor anti- 222 or gold-198, removable needles of radium-226, gens of sarcoids in vivo, apparently stimulating the cobalt-60, or iridium-192, and 192Ir seeds using an immune system to recognize them as foreign and after loading technique) has been used to treat mount a response quite similar to the host versus equine sarcoids. Responses range from 50% to graft rejection. It can become quite sore to the touch, but this sensitivity lasts only a few days. 100% sarcoid free for 1 yr, alone or in combination According to the manufacturer, XXTerra has been with surgical debulking and/or hyperthermia, espe- effective in Ͼ95% of the sarcoids treated. Total cially when the peri-orbital is involved. Fortu- failures have been observed in rare instances and nately, the treatment radiates the tumor locally and have been attributed to a non-functional immune spares adjacent healthy tissue. Disadvantages in- system. XXTerra seems safe on normal skin. The clude exposure for the surgeon, need for special product is applied 0.125- to 0.25-in thick over af- equipment, size of the tumor limiting its application, fected areas and then covered with a non-adherent poor local cosmesis (alopecia and leukotrichia), and Telfa pad and bandage. The procedure is repeated patient containment in a radiation safety approved every 4–6 days until the tumor is ready to slough area that increases costs. 15–20 (i.e., purulent debris and blood is noted). For sar- Intratumoral cisplatin (an emulsion of 10 mg coids located where a bandage cannot be used, the of powdered cisplatin, 1 ml of sterile saline, and 2 ml product is topically applied daily for 4–6 days and of patient’s serum, medical grade sesame or peanut then repeated at 4-day intervals until the tumor oil [resultant solution contains 3.3 mg of cisplatin a sloughs. per milliliter], or aqueous cisplatin [Platinol at 1 AW–3–LUDES,21,c a topical proprietary ointment mg/ml]) has proven successful as a sole chemother- containing a variety of heavy metals and the antim- apeutic treatment or when performed after debulk- itotic compounds 5-fluorouracil and thiouracil, is ad- ing the tumor. The procedure involves pre-treating ministered on successive or alternate days for 3–5 the area with local anesthetic and then injecting the treatments. Within 5–10 wk, preferential necrosis mixture into multiple planes no further than 0.6–1 and sloughing of the sarcoid tissues should be noted. cm apart at the base of the tumor and surrounding tissue at a dose rate of 0.97 mg of cisplatin/cm2 of 11. Immunomodulatory Approach tissue every 2 wk through four injections using Luer Bacillus of Calmette and Guerin (BCG; Regressin- locked small gauge needles (22–25 gauge). It has Vd),9,22 cell wall fractions of an attenuated strain of been reported that 87% of these horses have not Mycobacterium bovis, acts as an immunomodulator relapsed after one year. Disadvantages include that stimulates host lymphocyte and natural killer need for safety precautions (chemotherapy gear, cells. Optimal results are obtained if this product Luer lock syringes, latex gloves, protective eyewear, is used in an immunocompetent host with limited surgical masks, and biohazard disposal), potential tumor burden or post-debulking in the periocular for secondary peri-injectional infections, and oc- region. An 83.5% (10 of 12) rate of remission has currence of some degree of tissue sloughing and been achieved with periocular sarcoids, whereas use perilesional swelling. A serious human health on all other body regions resulted in a 48.5% rate of concern is the potential for carcinogenicity and remission. After two or more injections, swelling teratogenicity of all those handling treated horses, occurs within minutes or hours and may be exten- including extruded drug and the patient’s sweat, sive. Inflammation progresses to necrosis and ul- urine, and/or feces. At this time, post-chemo- ceration of the tumor along with pyrexia, therapeutic treatment quarantine times have not , non-fatal anaphylaxis, severe local in- been addressed. Recently, cisplatin injections flammatory reactions (including ), sep- have been combined with adjunctive therapies to tic arthritis, and general malaise in some cases. try to improve responses. Thus far, the addition Complete resolution of the process and tumor takes of a single high dose of interleukin-2 has not im- months (6 wk to 1 yr or more). Complications can proved efficacy over cisplatin injections alone include death from anaphylactic shock after two or (ϳ80%). However, cisplatin intralesional injec- more injections. Therefore, pre-medication with tions followed by electropulsation (improves diffu- flunixin meglumine and corticosteroids has been sion of chemotherapeutics through tumors) of recommended. An advantage is tumor specificity

AAEP PROCEEDINGS ր Vol. 52 ր 2006 481 IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY whereby only sarcoid cell necrosis is noted on his- made aware of their location along with the potential topathologic post-BCG evaluation. risk that even flat sarcoids may become malignant. Similarly, Propionibacterium acnes is a non-spe- cific immunostimulant that may induce macrophage References and Footnotes activation and lymphokine production, increase nat- 1. Scott DW, Miller WH. Neoplastic and non-neoplastic ural killer cell activity, and enhance cell mediated tumorsϪsarcoids. In: Scott DW, Miller WH, eds. Equine immunity against immunogenic components of dermatology. St. Louis: W.B. Saunders, 2003;720–732. equine sarcoids. Protocols vary from intralesional 2. Pascoe RRR, Knottenbelt DC. Manual of equine dermatol- to IV injections once weekly for 6–8 wk. Susceptible ogy. Neoplastic conditions. London: W.B. Saunders, 1999;241–267. lesions generally show improvement after two to three 3. Goodrich L, Gerber H, Marti E, et al. Equine sarcoids. treatments, and eventually, they necrose and slough. Vet Clin North Am [Equine Pract] 1998;14:607–621. Autogenous vaccination,23 using autogenous poly- 4. Foy JM, Rashmir-Raven AM, Brashier MK. Common merized tumor tissue combined with tuberculin pu- equine tumors. Compend Cont Educ Pract Vet 2002;24:242– 252. rified protein derivative as an adjuvant, resulted in 5. Chambers G, Ellsmore VA, O’Brien PM, et al. Association of complete regression in nine horses with refractory bovine papillomavirus with the equine sarcoid. J Gen Virol sarcoids. However, because the risks include tu- 2003;84:1055–1062. mor production and transmission of other diseases, 6. Chambers G, Ellsmore VA, O’Brien PM, et al. Sequence this procedure should only be attempted in the most variants of bovine papillomavirus E5 detected in equine sar- coids. Res 2003;96:141–145. refractory of cases and with individual patients 7. Knottenbelt DC. A suggested clinical classification for the known to be negative for equine infectious anemia. equine sarcoid. Clin Tech Equine Pract 2005;4:278–295. Imiquimod 5%g24 is an immune-response modifier 8. Knottenbelt DC, Kelly DF. The diagnosis and treatment of that was shown to have potent antiviral and antitu- periorbital sarcoid in the horse: 445 cases 1974 to 1999. Vet Ophthalmol 2000;3:169–191. mor activity in animal models and humans. Until 9. Martens A, De Moor A, Vlaminck L, et al. Evaluation of recently, the successful use of topical imiquimod in excision, cryosurgery and local BCG vaccination for treat- the treatment of equine sarcoids has been anecdot- ment of equine sarcoids. Vet Rec 2001;1:665–669. ally reported. An open label study evaluating the 10. Hanson RR. Cryotherapy for equine skin conditions. efficacy of topically applied imiquimod 5% cream (3 In: Robinson NE, ed. Current therapy in equine medicine, 4th ed. Philadelphia: W.B. Saunders, 1997;370–372. times per week) for the treatment of various equine 11. Carstanjen B, Jordan P, Lepage OM. Carbon dioxide laser sarcoids revealed a Ն75% reduction in tumor size in as a surgical instrument for sarcoid therapyϪa retrospective 13 of 16 (81.3%) tumors in the study over 8–24 wk; study on 60 cases. Can Vet J 1997;38:773–776. 9 of them (56.2%) showed complete resolution. 12. McCauley CT, Hawkins JF, Adams SB, et al. Use of a car- bon dioxide laser for surgical management of cutaneous The most common adverse effects included exudate, masses in horses: 32 cases (1993–2000). J Am Vet Med erythema, erosions, and alopecia, which were lim- Assoc 2002;220:1192–1197. ited to the tumor and adjacent areas. Based on these 13. Lucroy MD, Bartels KE. Using biomedical lasers in veteri- results, topical imiquimod seems to be a good thera- nary practice. Vet Med 2000;95(10):4–9. peutic option for the treatment of equine sarcoids and 14. Theon AP, Pascoe JR. Iridium-192 interstitial brachyther- apy for equine periocular tumors: treatment results and to prevent tumor transformation post-biopsy. prognostic factors in 115 horses. Equine Vet J 1995;27:117– 121. 12. Future Therapeutic Direction 15. Spoormakers TJ, Klein WR, Jacobs JJ, et al. Comparison of The positive response to the immunomodulator Al- the efficacy of local treatment of equine sarcoids with IL-2 or cisplatin/IL-2. Cancer Immunol Immunother 2003;52:179– dara supports the hypothesis of a viral component to 184. the etiology of sarcoids. Based on these findings 16. Rols MP, Tamzali Y, Teissie J. of and the response to non-specific immunomodulatory horses. A preliminary clinical report. Bioelectrochemistry agents, perhaps we should focus our treatment di- 2002;55:101–105. rection toward specific anti-viral agents (e.g., riba- 17. Theon AP. Intralesional and topical chemotherapy and im- munotherapy. Vet Clin North Am [Equine Pract] 1998;14: virin) and/or other specific anti-viral immune- 659–672. response modifiers (e.g., interferon), as opposed to 18. Theon AP, Pascoe JR, Madigan JE, et al. Comparison of toxic chemotherapeutic agents and expensive surgi- intratumoral administration of cisplatin versus bleomycin for cal extirpation. treatment of periocular squamous cell carcinomas in horses. Am J Vet Res 1997;58:431. 13. Client Education 19. Theon AP, Pascoe JR, Meagher DM. Perioperative intratu- moral administration of cisplatin for treatment of cutaneous Prognosis depends on many variables such as site, tumors in . J Am Vet Med Assoc 1994;205:1170– size, aggressiveness, number of lesions, number of 1176. treatment attempts, and location (legs and axillae ϭ 20. Theon AP, Pascoe JR, Carlson GP, et al. Intratumoral che- ϭ motherapy with cisplatin in oily emulsion in horses. JAm aggressive; periocular vulnerable). Failure to re- Vet Med Assoc 1993;202:261–267. solve the lesions frequently results in regrowth of 21. Newton SA. Periocular sarcoids in the horse: three cases the tumor, which may be more aggressive with exten- of successful treatment. Equine Vet Edu 2000;12:137–143. sive local infiltration and faster growth.8 Combined 22. Komaromy AM, Andrew SE, Brooks DE, et al. Periocular sarcoid in a horse. Vet Ophthalmol 2004;7:141–146. therapy may provide fewer chances of relapse. If sar- 23. Kinnunen RE, Tallberg T, Stenback H, et al. Equine sarcoid coids are noted on a pre-purchase examination, the tumour treated by autogenous tumour vaccine. Anticancer lesion(s) should be recorded, and owners should be Res 1999;19:3367–3374.

482 2006 ր Vol. 52 ր AAEP PROCEEDINGS IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY

24. Nogueira SAF, Torres SMF, Malone E, et al. Efficacy of imiquimod 5% cream in the treatment of equine sarcoids: a pilot study. Vet Dermatol 2006;17(4)259–265.

aPlatinol, Bristol Myers-Squibb Company, Princeton, NJ 08543. bXXTerra, Larson Laboratories, Inc, Fort Collins, CO 80524. cAW–3–LUDES, Liverpool University Department of Equine Surgery, Liverpool, UK L69 7ZX. dRegressin-V, BIONICHE Animal Health Canada Inc., Bel- leville, ON, Canada K8N 5J2. eEqStim, Neogen Corporation, Lexington, KY 40511. fImmunoregulin, Neogen Corporation, Lexington, KY 40511. gAldara, 3M Pharmaceuticals, St. Paul, MN 55144.

Aural Plaques

Anthony A. Yu, DVM, MS, Diplomate ACVD

1. Introduction virus has been shown through electron- microscopy and immunohistochemical techniques from lesions of aural plaques.1 It is suspected that biting insects may transmit the virus. Interest- ingly, biopsies of aural plaques may stimulate re- duction or resolution of lesions; however, this may only be temporary (6–12 mo). Possibly, it is caused by a release of “papilloma antigens” into the blood stream, which prompts an immune response against the plaques.

2. Signalment Fig. 1. Multiple smooth and raised depigmented plaques located There is no sex or breed prevalence, and horses of on the concave surface of the pinna are characteristic of equine any age can be affected; however, the disease is aural plaques. rarely seen in horses Ͻ1 yr of age.2–4 A study reported that 48 of 214 (22%) randomly examined horses were diagnosed with aural plaques.2 5. Treatment 3. Clinical Findings Aural plaques do not spontaneously regress. The response to topical application of tretinoin (Retin- Single to multiple, smooth or raised (up to 10 mm) Aa: 0.025%, 0.05%, or 0.1% cream and 0.01% or depigmented plaques (1–30 mm diameter) can be 0.025% gel) has been variable.3 Treatment is located bilaterally on the inner surface of the pinnae 2,3 typically directed at insect transmitted viruses. (Fig. 1). The lesions tend to coalesce and can Therefore, it includes interferon alpha-2a orally affect up to 40% of one or both ear-pinnae surfaces. (1000 IU/ml) and/or topically, topical iodine applica- Horses can be asymptomatic unless severely irritated tions (Xenodineb), and fly repellants (2% permethrin/ by biting flies, particularly black flies. Rarely, pyriproxyfen [Knockout L.A.c]). Griseofulvin, as an plaques may be seen around the anus, penis, and immune modulator, has been anecdotally helpful in vulva. Horses with this condition tend to be 1 yr of some cases.3 Trauma to the area (i.e., biopsies or age or older. scraping with a dull scalpel blade) may prompt an immune response against the plaque(s). 4. Diagnosis Imiquimod, an immune response modifier, shows Diagnosis in practice is based on a classic clinical potent antiviral and antitumor activity in animal appearance. Dermatopathology is pursued primar- models and humans.5,6 It has been used with great ily to rule out pre-cancerous stages of squamous cell efficacy in the treatment of external genital and carcinoma. Histopathology of aural plaques have perianal warts caused by papilloma virus in humans features consistent with papilloma virus infection, as well as other cutaneous viral infections, such as such as papillated epidermal hyperplasia, koilocy- , and skin tumors, such as tosis, and increased numbers and sizes of kerato- basal cell carcinoma, , and recently, hyalin granules.4 Other non-specific findings in situ.7–10 Imiquimod is include orthokeratotic and epider- currently recommended as a treatment modality for mal hypomelanosis. papillomas and herpes virus as well as Bowen’s dis-

AAEP PROCEEDINGS ր Vol. 52 ր 2006 483 IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY (squamous cell carcinoma in situ) in small an- tion is most likely caused by release of toxic eosino- imal dermatology.11 More recently, research into philic contents such as major basic protein. the use of imiquimod to treat equine sarcoids, also suspected to have a papilloma viral etiology, re- 2. Pathogenesis vealed 13 of 16 (81.3%) had a 75% reduction in size A large subset of affected horses represents hyper- within 8–24 wk.12 Based on the effects of imi- sensitivity reactions to insect bites. There is evi- quimod along with the similar pathogenesis of hu- dence to support this hypothesis. man warts and equine aural plaques, a multi-center investigation of imiquimod as a treatment for horses 1. Many affected horses have been diagnosed with aural plaques is underway. with Culicoides hypersensitivity. 2. Nodules recur each year with the onset of 6. Prognosis pruritus and the insect season and tend to Aural plaques tend to be persistent and rarely un- resolve in the winter or with insect control. dergo spontaneous regression. 3. Lesions occur at body sites on which insect feeding has been documented. References and Footnotes 1. Fairley RA, Haines DM. The electron microscopic and im- Other groups of affected horses were intradermal munohistochemical demonstration of a papillomavirus in allergy test positive for inhalants but not insects, equine aural plaques. Vet Pathol 1992;29:70–81. whereby allergen specific immunotherapy (ASIT) re- 2. Binninger CE, Piper RC. Hyperplastic dermatitis of equine sulted in resolution of clinical signs. This suggests ear. J Am Anim Med Assoc 1968;153:69–75. 3. Scott DW, Miller WR. Neoplastic and non-neoplastic tu- that atopic dermatitis is a potential underlying eti- mors. In: Scott DW, Miller WR, eds. Equine dermatology. ology. Food allergies have also been proposed; di- Philadelphia: W.B. Saunders, 2003;700–707. etary trials have resulted in resolution of clinical 4. Williams MA. : warts and aural plaques. signs, and rechallenge resulted in relapse. Overall, In: Robinson ME, ed. Current therapy in equine medicine IV. Philadelphia: W.B. Saunders, 1997;389. similar to cats, eosinophilic tend to be a 5. Gollnick H, Barasso R, Jappe U, et al. Safety and efficacy of reaction pattern attributable to an allergic etiology. 5% imiquimod cream in the treatment of penile genital warts In fact, injection site granulomas were reported in in uncircumcised men when applied three times weekly or response to the silicone coating on hypodermic nee- once per day. Int J STD AIDS 2001;12:22–28. dles (Fig. 1).2 Future reactions were avoided by 6. Beutner KR, Tyring SK, Trofatter JR, et al. Imiquimod, a patient-applied immune-response modifier for treatment of using uncoated stainless steel needles. external genital warts. Antimicrob Agents Chemother 1998; 42:789–794. 3. Clinical Findings 7. Berman B, Hengge U, Barton S. Successful management of As mentioned previously, nodules usually appear in viral infections and other dermatoses with imiquimod 5% cream. Acta Derm Venereol 2003;214(Suppl):12–17. the warmer months of the year, although geographic 8. Nouri K, O’Connell C, Rivas MP. Imiquimod for the treat- variations exist, and males are more frequently af- ment of Bowen’s disease and invasive squamous cell carci- fected.3 One or multiple lesions, which vary in size noma. J Drugs Dermatol 2003;2:669–673. from 1–10 cm, typically are round and firm with no 9. Orengo I, Rosen T, Guill CK. Treatment of squamous cell , alopecia, or ulceration noted carcinoma in situ of the penis with 5% imiquimod cream: a case report. J Am Acad Dermatol 2002;47:S225ϪS228. (Fig. 2). Atypical lesions may ulcerate and drain, 10. Schroeder TL, Sengelman RD. Squamous cell carcinoma in whereas some may be cystic or plaque-like with a situ of the penis successfully treated with imiquimod 5% central caseous or calcified core. The neck, withers, cream. J Am Acad Dermatol 2002;46:545–548. saddle, and girth are the most affected areas. Mul- 11. Medleau L, Hnilica KA. Small animal dermatology: a tiple lesions (sometimes hundreds) on one side of the color atlas and therapeutic guide, 2nd ed. St. Louis: 1 Elsevier Inc., 2006. body only have been rarely reported. 12. Nogueira SAF, Torres SMF, Malone ED, et al. Efficacy of imiquimod 5% cream in the treatment of equine sarcoids: a 4. Diagnosis pilot study. Vet Dermatol 2006;17(4):259–265. History, palpation, and clinical appearance are very

a suggestive. Confirming the diagnosis requires der- Retin-A, Ortho, Marysville, OH 43040. matopathologic evidence of a granulomatous reac- bXenodine, Veterinary Products Laboratories, Phoenix, AZ 85067-4820. tion and the appearance of flame figures around cKnockout L.A., Virbac AH, Inc., Fort Worth, TX 76137. collagen bundles consisting of eosinophils and eosin- ophilic granules or “mush.”4 Calcification can be Eosinophilic (Nodular Necrobiosis) observed in older lesions. Notably, the equine eo- sinophilic granuloma is histologically similar in ap- Anthony A. Yu, DVM, MS, Diplomate ACVD pearance to the linear granuloma lesions in cats.

1. Introduction 5. Treatment Eosinophilic granulomas are the most common non- Glucocorticoids are the principal means of treating neoplastic nodular disease in horses and are char- these lesions. If a single lesion is noted, intrale- acterized by intense eosinophilic infiltrates.1 The sional or sublesional injection of 5 mg triamcinolone collagen degeneration that accompanies this condi- acetonide for 2 wk with 3 treatments provides a

484 2006 ր Vol. 52 ր AAEP PROCEEDINGS IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY ing laminitis and other adverse effects associated with the use of glucocorticoid exists, surgical extir- pation or CO2 LASER ablation should be considered. When multiple lesions are present, prednisolone 1–2 mg/kg/day for 7–10 days with tapering completely off medication within 3–4 wk is likely with this condition, especially if the underlying etiology is addressed (i.e., ectoparasite control, dietary trial, and ASIT).

References 1. Scott DW, Miller WH. Eosinophilic granuloma. In: Equine dermatology. Philadelphia: W.B. Saunders, 2003; 647–651. 2. Slovis NM, Watson JL, Affolter VK, et al. Injection site eosinophilic granulomas and collagenolysis in 3 horses. J Vet Int Med 1999;13:606–612. 3. Valentine BA Equine cutaneous non-neoplastic nodular and proliferative lesions in the Pacific Northwest. Vet Dermatol 2005;16:425–428. 4. Fernandez CJ, Scott DW, Erb HN. Staining abnormalities of dermal collagen in eosinophil or neutrophil-rich inflamma- tory dermatoses of horses and cats as demonstrated with Masson’s trichrome stain. Vet Dermatol 2000;11:43–48.

Urticaria

Anthony A. Yu, DVM, MS, Diplomate ACVD

1. Introduction Of all domestic animals, horses show the greatest incidence of urticaria and .1 Similar to the eosinophilic granuloma complex in cats, urti- caria and angioedema in horses are symptoms but not a diagnosis. The real challenge is to identify Fig. 1. Multiple firm, haired nodular lesions in the jugular and eliminate/address the underlying etiology of groove post-venipuncture are used for routine bloodwork with standard silicone coated needles. this condition. For this reason, urticaria and an- gioedema are some of the most common dermato- logic conditions referred to a veterinary equine dermatology practice. Urticaria and angioedema occur as a result of mast cell and basophil degranulation in response to either an immunologic or non-immunologic stimulus. Immunologic reactions, typically type immunoglobulin E (IgE) associated or type-III hy- persensitivity, may result from allergens that are ingested (food allergy), inhaled (atopy), injected (in- sect hypersensitivity), or percutaneously absorbed (contact allergy or drug reaction). Non-immuno- logic factors that may intensify reactions in horses include psychologic stresses, genetic abnormalities, various drugs and chemicals (e.g., , narcotics, foods, or food additives), temperature related urti- caria (heat, cold, or sunlight), physical urticaria (pressure or dermatographism), and exercise-in- Fig. 2. Multiple firm, haired to excoriated nodular lesions of vary- duced urticaria.1,2 Regardless of the inciting fac- ing sizes on the neck of a horse with equine eosinophilic granulomas. tor, basophil and mast cell release of inflammatory mediators (histamine, platelet activating factor, and prostaglandins) cause increased vascular smooth muscle cell relaxation and endothelial cell retrac- non-surgical alternative. If an incomplete resolu- tion, which allows plasma to extravasate and form tion is noted with this protocol or if concern regard- cutaneous wheals or angioedema.3

AAEP PROCEEDINGS ր Vol. 52 ր 2006 485 IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY 2. Signalment There seems to be no characteristic signalment as- sociated with the development of urticaria or angio- edema. Thoroughbred and Arabian horses between 1 and 10 yr of age seem to be affected frequently because of their increased predisposition to allergic dermatitis.

3. Clinical Findings Pitting edema is the key clinical feature of urticaria and angioedema, although some hives can be quite firm on palpation. Inflammatory lesions, tumors, and fluid filled swellings do not pit on compression. The onset of clinical lesions can be acute or peracute within minutes to hours post challenge from expo- sure to the inciting factor. Pruritus is variable. The overlying skin is normal, and there is no alope- Fig. 1. Conventional urticaria with mixed papular and wheal cia. Lesions vary in shape and size and may lesions involving the face and neck of a pollen sensitive horse. present as papular, annular, giant, or gyrate (ser- piginous, linear, or arciform) wheals (Figs. 1 and 2; Table 1). In cases with severe dermal edema, ooz- 5. Diagnosis ing of serum from the skin surface and possibly, cracking and superficial sloughing of the hair and Based on the extensive list of potential causes, a skin that resembles pyoderma and may be veterinarian’s task can seem ominous. Careful ex- noted.1 Angioedematous reactions are SC, local- amination of the horse’s history and environment ized to generalized, gravity dependent fluid swell- are key to establishing a possible etiology. For in- ings that are variably pruritic, and may have serum stance, the sudden onset of wheals associated with leakage or hemorrhage. The pattern of distribu- the administration of a drug renders the cause tion includes the head, extremities, and, ventral ab- readily apparent. A protracted history may be domen and thorax. Angioedema may be a more difficult to decipher, because eruptions wax and wane, environmental challenges occur daily, cutaneous manifestation of systemic and/or serious and medications are often used concurrently with disease. feed supplements. 4. Underlying Etiologies Urticaria and angioedema are symptoms rather than specific disease entities. It is often seen just before races (perhaps psychogenic) or in association with insect or arthropod envenomation, various in- fections (strangles, dermatophytosis, dermatophilo- sis, dourine, babesiasis, surra, horse pox, or mal de caderas), intestinal parasitism (Cyathostomosis), topical applications (especially parasiticidal sprays, dips, and pour-ons), systemic medicaments (espe- cially trimethoprim potentiated sulfonamides, penicillin, phenylbutazone, ivermectin, aspirin, guaiphenesin, , streptomycin, oxytet- racycline, gas anesthesia, or iron dextrans), feed- stuffs (pasture plants or concentrates), contactants (saddle soaps, leather conditioners, or tack), various biologicals (strangles, encephalomyelitis, and salmo- nellosis or botulinum and tetanus toxoids), snake bites, hypodermiasis, , inhalants (pollens, molds, or chemicals), hemorrhagica, plants (stinging nettle), hematoma (especially hemophiliacs), lymphangitis, abscess/ pyoderma, cellulitis, vasculitis (immune mediated and photoactivated), lymphoreticular neoplasia, Fig. 2. Conventional urticaria with mixed papular and wheal mast cell tumor, or amyloidosis.1,2,4–10 lesions involving the trunk of pollen sensitive horse in Fig. 1.

486 2006 ր Vol. 52 ր AAEP PROCEEDINGS IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY ever, the horse had negative findings on special stains.4 Successful treatment was achieved with antifungal therapy for the dermatophytosis and IV dexamethasone for the urticaria. It was suspected that the ringworm infection resulted in an “id” reac- tion, an immunologic response of the skin to system- ically absorbed fungal antigens. In this author’s opinion, allergy testing for urti- caria is warranted if the history coincides with a clinical case that is recurrent or persists for Ͼ8 wk. Allergy testing should not be used to diagnose atopy. Rather, it is a means of confirming your clinical suspicions and formulating a treatment plan involv- ing both avoidance and allergen specific immuno- therapy. Positive reactions indicate that antigen specific IgE is present in the patient; it does not indicate that the antigen in question caused the Fig. 3. Intradermal allergy test in horse from Fig. 1 with posi- disease. Therefore, careful historical evaluation tive reactions to primarily pollens (trees, grasses and weeds). and correlation with reactions is important for hy- posensitization success. Serologic testing is avail- able through Greer Laboratories,a Spectrum Laboratories,b Heska Corporation,c and Bio-Medical Physical urticaria (dermatographism) is easily Services.d Serologic testing can be quite expensive; distinguished by drawing a pattern on the skin with however, recent series of studies from the Ohio State a blunt object. Within 10–15 min, a positive reac- University concurred with previous findings that tion is denoted by marked edematous swelling of the intradermal allergy testing is more reliable than inscribed pattern. Historical evidence of dermatog- serologic testing.13–16 raphism includes swelling involving areas of light Intradermal allergy testing (IDT) does require se- pressure such as under the saddle, , or girth. dation, , withdrawal from essential fatty ac- Temperature sensitive urticaria will similarly de- ids, antihistamines, and topical steroids for 7–14 velop edematous swelling within 15 min of cold (ice days, and withdrawal from oral/injectable glucocor- cube) or heat (hot pack warmers) application to ticoids for 7–28 days. This author has performed the skin. Exercise-induced urticaria and cholin- IDT on cases that have received injectable diphen- ergic urticaria are easily confused. Cholinergic ur- hydramine and glucocorticoids shortly before allergy ticaria results from an increase, either active testing, and significant results were still obtained (exercise related) or passive (hot bath), in body core (Fig. 3). Therefore, withdrawal from anti-inflam- temperature, whereas exercise-induced urticaria re- matory medications does not seem as crucial in quires the active stimulus of exercise.4,11 horses as it does in dogs and cats. A detailed re- Skin scrapings, fungal cultures, impression view of the testing method has recently been re- smears, and serology are valuable diagnostic tools if viewed.13–16 The tests are tailored to specific an infectious etiology is suspected. Biopsies may geographic regions using small animal test concen- help to rule out other potential etiologies. Biopsies trations/allergens with additional insects and out- are recommended when the lesions are firmer than door allergens to account for the horse’s exposure. expected or when the disease has been ongoing (Ͼ2 This author tends to read test reactions at 30 min mo). A dermatopathologist with an interest in and 4 h after inoculation and omits the 24-m and equine dermatology is advised, especially if second- 48-h reactions because of the questionable value of ary self-inflicted trauma is involved. Typical his- the delayed responses for immunotherapy and fea- topathologic findings of urticaria or angioedema sibility in practice. Evaluating size and especially vary from a simple vascular dilatation and edema in turgidity of the wheals is very important, and it the superficial and middle dermis to pure perivas- requires the expertise of an allergist to minimize cular dermatitis with varying numbers of mononu- false positive/negative reactions.17 clear cells, neutrophils, mast cells, and eosinophils.2 Dietary trials are the only way to diagnose food In challenging cases, immunohistochemical evalua- hypersensitivity or intolerance. The author’s cur- tion of IgE bearing cells may distinguish between rent approach consists of a 4–6-wk trial with novel common clinical differentials, such as insect bite food sources such as timothy, rolled oats, alfalfa, or hypersensitivity, and pemphigus.12 Laboratory barley, if not routinely fed, because these items are tests may provide confusing results when evaluating easily obtainable single source foods. Discontinua- urticaria and angioedema. This is exemplified by a tion of unnecessary supplements, vitamins, and case of a Paso Fino that was cultured der- other drugs is mandatory throughout the trial pe- matophyte positive (Trichophyton mentagrophytes) riod. After the urticaria has resolved, confirmation and histologically diagnosed with urticaria; how- of food allergy is achieved by challenging with one

AAEP PROCEEDINGS ր Vol. 52 ր 2006 487 IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY

Table 1. Clinical Classification of Urticaria/Angioedema

I. Conventional urticaria: a. Papules and wheals that vary from 2 mm to 5 cm in diameter. II. Papular urticaria: a. Small, 3 to 6-mm-diameter papules b. Most often associated with stinging insects, especially and culicoides. III. Giant urticaria: a. Large wheals up to 20–40 cm in diameter b. Consider vasculitis a serious differential/complication IV. Exudative urticaria: a. Severe dermal edema oozes from the skin, mats the hairs, and eventually causes alopecia. b. Often mistaken for pyoderma or pemphigus V. Gyrate (polycyclic) urticaria: a. Arciform, serpiginous, or doughnut shaped b. Often associated with drug reactions c. Can persist for months d. Major differential is erythema multiforme that typically do not exhibit pitting with digital pressure. VI. Angioedema (angioneurotic edema): a. Involves large areas of subcutaneous tissues b. More diffuse and involves the head and/or gravity dependent extremities c. Cutaneous marker for a more systemic and serious disease than urticaria.

item weekly and monitoring for exacerbation of clin- therapy includes antihistamines, essential fatty ac- ical signs (typically 24–72 h). ids, and glucocorticoids (Table 2). For chronic cases Unless a specific etiology is identified, treatment where an allergic dermatitis is suspected, allergen is often frustrating, because recurrences are com- specific immunotherapy (ASIT) provides optimal re- mon. Acute cases of idiopathic urticaria can be sponses, and it can be used to address not only treated successfully with antihistamines, glucocor- urticaria but also pruritus and recurrent airway ticoids, and/or epinephrine. The optimal treatment obstruction (RAO) cases. ASIT carries the fewest involves avoidance or reduced allergen exposure. long-term side effects, provides more rapid re- Unfortunately, this is often impractical but may in- sponses than those seen in dogs and cats, and clude moving to a different part of the country or provides the most cost-effective and least treat- simply down the road to another stable, restricting ment intensive option compared with symptom- indoor/outdoor activity (depending on IDT reac- atic therapy in horses. ASIT also provides an tions), and/or providing rubber mats and pelleted alternative treatment modality that precludes rations to decrease dust. Short-term symptomatic drug testing and allows competitive horses to re-

Table 2. Symptomatic Treatment of Urticaria/Angioedema

Epinephrine 3 to 5 ml of a 1:100 solution, SQ or IM Lifesaving for severe angioedematous reactions Antihistamines Hydroxyzine hydrochloride @ 1–1.5 mg/kgq8h Doxepin hydrochloride @ 0.5–0.75 mg/kg q 12 h Diphenhydramine @ 0.75–1 mg/kg q 12 h Chlorpheniramine @ 0.25 mg/kg q 12 h Side effects include light sedation, occasional personality changes, ϩ/Ϫ teratogenicity AQHA recommended withdrawal is 10 days before any show or competition Corticosteroids Prednisolone 0.5–1.5 mg/kg/day 7–14 days, then taper to 0.2–0.5 mg/kg q 48 h over 2–5 wk Dexamethasone Loading/pulse dose at 0.02–0.1 mg/kg/day IV for 2–3 days, then oral maintenance dose of 0.01–0.02 mg/kg q 48–72 h This regimen is particularly helpful in more refractory cases Fatty acid supplementation DVMs Derm Caps or 3VCaps Liquid Econo @ double the dose/day Allerderms EFA Caps HP @ double the dose/day Vet Solutions EFA @ 2 2/3 pumps per 50 kg/day

488 2006 ր Vol. 52 ր AAEP PROCEEDINGS IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY turn to performance standards without jeopardiz- 8. Bathe AP. An unusual manifestation of nettle in three ing the owner’s ethics. horses. Vet Rec 1994;134:11–12. 9. Matthews NS, Light GS, Sanders EA, et al. Urticarial re- sponse during anesthesia in a horse. Equine Vet J 1993;25: 6. Prognosis 555–556. The prognosis for urticarial reactions is good, be- 10. Paul JW. Equine larval cyathostomosis. Compend Cont Educ Pract Vet 1998;20:509–515. cause general health is not usually affected. The 11. Logas D, Kunkle GA, Calderwood-Mays MB, et al. Cholinergic prognosis for angioedema varies with the severity pruritus in a horse. J Am Vet Med Assoc 1992;201:90–91. and location. Angioedematous reactions involving 12. Rufenacht S, Marti E, von Tscharner C, et al. Immuno- the nasal passages, pharynx, and larynx may be globulin E-bearing cells and mast cells in skin biopsies of horses with urticaria. Vet Dermatol 2005;16:94–101. fatal if not immediately addressed. 13. Delger JM. Intradermal testing and immunotherapy in horses. Vet Med 1997;92:635–639. References and Footnotes 14. Lorch G, Hillier A, Kwochka KW, et al. Comparison of im- mediate intradermal test reactivity with serum IgE quanti- 1. Pascoe RRR, Knottenbelt DC. Manual of equine dermatology. tation by use of a radioallergosorbent test and two ELISA in Immune-mediated/allergicdiseases. London: Harcourt Brace horses with and without atopy. J Am Vet Med Assoc 2001; and Company, 1999;156–160. 218:1314–1322. 2. Scott, DW, Miller, WH. Skin immune system and allergic 15. Lorch G, Hillier A, Kwochka KW, et al. Results of intrader- skin disease. In: Equine dermatology. London: W.B. mal tests in horses without atopy and horses with chronic Saunders, 2003;422–427. obstructive pulmonary disease. Am J Vet Res 2001;62:389– 3. Abbas AK, Lichtman AH, Pober JS. Cellular and molecular 397. immunology. Philadelphia: W.B. Saunders, 1991;294. 16. Lorch G, Hillier A, Kwochka KW, et al. Results of intrader- 4. Fadok VA. Overview of equine papular and nodular derma- mal tests in horses without atopy and horses with atopic toses. Vet Clin North Am [Equine Pract] 1995;11:61–74. dermatitis or recurrent urticaria. Am J Vet Res 2001;62: 5. Fadok VA. Update on equine allergies. J Vet Allergy Clin 1051–1059. Immunol 1997;5:68–76. 17. Yu AA. Equine urticaria: a diagnostic dilemma. Com- 6. Scott DW, Miller WH. Idiosyncratic cutaneous adverse drug pend Cont Educ Pract Vet 2000;22:277–280. reactions in the horse: literature review and report of 19 cases (1990–1996). Equine Pract 1997;19:12–18. aGreer Laboratories, Lenoir, NC 28645. 7. Scott DW, Miller WH. Erythema multiforme in the horse: bSpectrum Laboratories, Mesa, AZ 85204. literature review and report of 9 cases (1988–1996). Equine cHeska Corporation, Fort Collins, CO 80525. Pract 1998;20:6–9. dBio-Medical Services, Austin, TX 78759.

AAEP PROCEEDINGS ր Vol. 52 ր 2006 489 IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY III. Crusting and Ulcerative Lesions

Cutaneous Equine Sarcoidosis (a Subset of lia, Coccidioides, Cryptococcus, and Corynebacte- Equine Idiopathic Granulomatous Disease [IGD]) ria has not been determined using histopathology, immunohistochemistry, or polymerase chain.6 Anthony A. Yu, DVM, MS, Diplomate ACVD A response to steroids would mean that CES is caused by an immune mediated reaction rather than infectious etiology. 1. Introduction Cutaneous equine sarcoidosis (CES) is a subset of 2. Signalment equine idiopathic granulomatous disease (IGD). Although no age, sex, or breed predisposition has Also referred to as systemic granulomatous dis- been cited in literature, a recent study did reveal a ease, generalized granulomatous disease, equine predisposition in gelding Thoroughbreds when nine histiocytic disease, and equine histiocytic derma- 1–8 cases were reviewed over 16 yr. Again, this may be titis, CES is a rare condition in horses. CES is a regional variant skewed by the referral hospital an idiopathic scaling and crusting disorder that population.1–8 Ages ranged from 5 to 21 yr.6 histopathologically resembles the condition de- scribed in humans, which is believed to be an aberrant reaction to an infectious agent/anti- 3. Clinical Findings gen.1–8 A similar reaction pattern occurs in the Cutaneous lesions typically start with crusts, scales, lungs (granulomatous pneumonia [GP]) and gas- alopecia, and pruritus involving the limbs (legs, trointestinal system (granulomatous enteritis thighs, and elbows), thorax, neck, head/face, ventral [GE]) in horses.9,10 In a recent review of nine abdomen, back, and ears and spread gradually to horses with CES, skin lesions were found on cause a generalized exfoliative dermatitis sparing horses with GE and GP, and 5 of 9 CES cases also the mane and tail (Figs. 1 and 2). Although re- had lung involvement.6 It has been proposed to ported, nodular lesions are quite rare. Peripheral classify the three subsets under an encompassing , however, is quite common. Rec- term of equine IGD.8 ognition of the cutaneous lesions prompts the clini- Hairy vetch (Vincia villosa) has been reported to cian to investigate other organ involvement, produce a similar reaction pattern in cattle and particularly the respiratory and gastrointestinal horses; however, many subsequent cases have not systems and to a lesser extent, the liver and kidneys. had this risk factor.11,12 Thus far, an infectious Weight loss, intractable diarrhea, exercise intoler- etiology for CES, including Mycobacteria, Borre- ance, dyspnea, diminished appetite, ventral edema,

Fig. 1. Generalized abundant scale with clumping and loss of hairs in a horse with sarcoidosis.

490 2006 ր Vol. 52 ր AAEP PROCEEDINGS IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY If malabsorption/GE is present, it is recommended that medications be given parenterally where possible. Also included in my initial protocol are the use of essential fatty acids, shampoo therapy, and pentoxi- fylline. Adding essential fatty acidsa at the recom- mended daily dose may help reduce the scaling by replenishing the corneal lipid envelope and provid- ing membrane stabilizing effects. Shampoo ther- apy (Universal Medicated Shampoob or Seboluxc) enhances keratolysis and keratoplasty and provides topical antimicrobial protection. Pentoxifylline (10 mg/kg, q 8–12 h) has rheologic activity that may improve drug delivery into granulomatous tissue and minimize the risk of laminitis while administer- ing steroids. Additionally, pentoxifylline has anti- inflammatory properties, namely anti-tumor necrosis factor-␣, which potentially allows for a syn- Fig. 2. Close-up of horse in Fig 1. with sarcoidosis. Note the ergistic tapering of steroids. Some cases of CES sheets of scale emanating from the skin and caught in the hairs, have spontaneously resolved, and therefore, taper- characteristic of an advanced case of sarcoidosis. ing of medications to the lowest dose possible or in total is always advised.2,7 If minimal response is noted to the above protocol, and low-grade fever indicate multiple organ adding azathioprine (3 mg/kg daily) for 30–60 days involvement.9,10 and then tapering to every other day alternating with steroids may provide some benefit. Systemic 4. Differential Diagnoses antibiotics should always be considered in severe Differentials based on clinical findings include mul- generalized cases (trimethoprim sulfa, 15–30 mg/kg, tisystemic eosinophilic epitheliotropic dermatitis q 12 h for 30 days) where a primary or secondary and stomatitis, eosinophilic gastroenterocolitis and infection may be suspected. dermatitis, lymphocytic plasmacytic enterocolitis, dermatophilosis, recurrent airway obstruction, der- 7. Prognosis matophytosis, , contact derma- The prognosis for cases limited to cutaneous involve- titis, drug eruptions, and toxicoses (arsenic or ment tends to be better (Ն12 yr) than those with iodine), depending on the organs involved. concurrent internal organ disease, especially if signs of weight loss/wasting exist.6 As spontaneous re- 5. Diagnosis mission has been reported, treatment should be at- Based on history, physical examination, tempted in all cases.6,7 Most horses with internal aspirates, and dermatopathology, a diagnosis of involvement, however, tend to decline over several CES can be made. Typically, the complete blood months and are eventually humanely euthanized. count (CBC) and chemistry profile reveal a neutro- philia, hyperfibrinogenemia, and hyperproteinemia References and Footnotes 13 consistent with an inflammatory condition. 1. Stannard T. Immunologic diseases. Vet Dermatol 2000;11: Peripheral circulating eosinophilia is rarely seen. 163–178. Bacterial and fungal cultures have classically been 2. Scott DW, Miller WH. Miscellaneous skin diseases. In: negative. Dermatohistopathologic findings include Scott DW, Miller WH, eds. Equine dermatology. St. Louis: W.B. Saunders, 2003;647–697. perifollicular mid-dermal sarcoid type granulomas 3. Heath SE, Bell RJ, Clark EG, et al. Idiopathic granuloma- with many histiocytic cells, superficial dermal infil- tous disease involving the skin in a horse. J Am Vet Med trate of multinucleated histiocytic giant cells, and a Assoc 1990;197:1033–1036. smaller number of superficial dermal neutrophils, 4. Sellers RS, Toribio RE, Blomme EA. Idiopathic systemic 1–7 granulomatous disease and macrophage expression of PTHrP lymphocytes, and plasma cells. in a miniature pony. J Comp Pathol 2001;125:214–218. 5. Axon JE, Robinson P, Lucas J. Generalised granulomatous 6. Treatment disease in a horse. Aust Vet J 2004;82:48–51. Currently, as in human medicine, there is no universal 6. Spiegel IB, White SD, Foley JE, et al. A retrospective study effective treatment for IGD/sarcoidosis (information of cutaneous equine sarcoidosis and its potential infectious aetiological agents. Vet Dermatol 2006;17:51–62. available online at http://www.nhlbi.nih.gov/health/ 7. Loewenstein C, Bettenay SV, Mueller RS. A retrospective public/lung/other/sarcoidosis). Immunosuppres- study of equine sarcoidosis. Vet Dermatol 2004;15:67. sive doses of steroids have been the mainstay with 8. Petersen AD, Schott HC. Cutaneous markers of disorders inconsistent results. Prednisolone (2.2–4.4 mg/kg affecting adult horses. Clinical techniques in equine prac- tice. 2005;4:324–338. daily) or dexamethasone (0.1–0.2 mg/kg daily) for 9. Schumacher J, Edwards JF, Cohen ND. Chronic idiopathic 7–14 days with tapering doses when or if an improve- inflammatory bowel diseases of the horse. J Vet Int Med ment is noted tends to be the first line of treatment. 2000;14(3):258–265.

AAEP PROCEEDINGS ր Vol. 52 ր 2006 491 IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY 10. Pusterla N, Pesavento PA, Smith P, et al. Idiopathic gran- pathways and then incites acantholysis.3 A sim- ulomatous pneumonia in seven horses. Vet Rec 2003;153: ilar pathway is hypothesized for the dog and horse 653–655. 11. Anderson CA, Divers TJ. Systemic granulomatous inflam- based on the detection of DSG1 in immunoblotting/ mation in a horse grazing hairy vetch. J Am Vet Med Assoc immunoprecipitation studies.4,5 Several trigger 1983;183:569–570. factors have been proposed including drugs, sys- 12. Woods LW, Johnson B, Hietala SK, et al. Systemic granu- lomatous disease in a horse grazing pasture containing vetch temic disease, neoplasia, stressful situations, and (Vicia sp.). J Vet Diag Invest 1992;4(3):356–360. lastly, allergies (foods, inhalants, insects) based 13. Lindberg R, Persson SG, Jones B, et al. Clinical and patho- on the presence of case clusters and seasonality physiological features of granulomatous enteritis and eosin- (Figs. 1–5).1,6 ophilic granulomatosis in the horse. Zentralbl Vet Med A 1985;32:526–539. 2. Signalment aDermCaps Liquid Econo, DVM, Miami, FL 33169. bUniversal Medicated Shampoo, Vet Solutions, Fort Worth, TX Pemphigus presents in both adult horses (Ն5yrof 76137. age) and foals (Ͻyr of age).7,8 This age dichotomy c Sebolux, Virbac AH, Inc., Fort Worth, TX 76137. may not be obvious in all populations.6 Younger Pemphigus horses often carry a better prognosis and potential for spontaneous remission without relapses. Of Anthony A. Yu, DVM, MS, Diplomate ACVD the specific horse breeds, Appaloosas, Quarter Horses, and Thoroughbreds seem to be at greater 1. Introduction risk, although this may have some geographic variabil- 1,6,7 Pemphigus foliaceus, first described in this species ity. At this time, there does not seem to be any in 1981, is the most common autoimmune skin evidence of sex predilection. Pemphigus has been disease in the horse.1,2 Several forms of pemphi- known to have a waxing and waning course, and there gus exist including pemphigus foliaceus, pemphi- may also be a seasonal incidence of the condition, poten- gus vulgaris (very rare), drug-induced pemphigus, tially caused by allergen load (pollens, insects) and/or the and paraneoplastic pemphigus. The most com- increased use of preventative medications (dewormers, monly reported form is that of pemphigus folia- vaccines, supplements, etc.).6,9 ceus. Pemphigus foliaceus in humans is a result of the production of autoantibodies directed 3. Clinical Signs against cell adhesion proteins, particularly the desmosomal antigens (desmoglein 1 [DSG1] in Classic clinical findings of vesicles and pustules pemphigus foliaceus and DSG3 in pemphigus vul- are rarely noted in the horse, because lesions of garis) of the stratified squamous epithelium. The pemphigus progress rapidly to crusts, exfoliation, antibody antigen complex moves through multiple erosions, alopecia, and scaling (Fig. 6). In fact,

Fig. 1. Equine pemphigus foliaceus with generalized crusts, exfoliation, erosions, alopecia, and scaling in a horse that was pruritic and responded poorly to treatment.

492 2006 ր Vol. 52 ր AAEP PROCEEDINGS IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY

Fig. 2. The horse in Figure 1 with the lip margins.

Fig. 4. The distribution and appearance of lesions in this horse over the trunk and face mimic that of a severe allergic case, beckoning the question whether hypersensitivities may be a trig- ger for pemphigus or a potential sequella of an incompletely managed chronic inflammatory condition.

transient, persistent, or recurrent urticaria may pre- cede actual crusts.1 Pruritus, pain, and edema re- sulting in a stiff gaited lameness are variable. Lesions tend to begin on the face or limbs and spread to the rest of the body in days to weeks (Figs. 7–12). A localized form restricted to the coronary can also be seen. Mucosal lesions are extremely rare. Although internal organs are not involved, systemic signs including depression, poor appetite, weight loss, fever, and lethargy are often noted and expressed in the complete blood count (CBC) and serum chemistry profile changes including anemia, leukocytosis, neu- trophilia, hyperglobulinemia, and hypoalbuminemia.

4. Differential Diagnosis Fig. 3. The distribution in this horse, along with his intractable pruritus, brings into question the possibility of insect bite hyper- Differential diagnoses include dermatophilosis, sensitivity as a trigger for pemphigus. dermatophytosis, Staphylococcal folliculitis, sys-

AAEP PROCEEDINGS ր Vol. 52 ր 2006 493 IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY

Figs. 7–12. Lesion distribution of severe generalized pemphi- gus involving the mucocutaneous regions (Figs. 9 and 10) and haired skin over the face and trunk (Figs. 7, 8, 11, 12). Le- sions reappeared within 1 week of discontinuing therapy. A combination of pentoxifylline, alternate day prednisolone and azathioprine had previously completely controlled the clinical signs.

temic granulomatous disease/equine sarcoidosis, multisystemic exfoliative eosinophilic dermatitis and stomatitis, , external parasite hypersensitivity, and keratinization disorders.

5. Diagnosis Diagnosis is based on history, clinical findings, skin Fig. 5. The distribution and appearance of lesions in this horse cytology, and dermatohistopathologic findings. over the trunk and face mimic that of a severe allergic case, Cytologic sampling is ideally performed from intact beckoning the question whether hypersensitivities may be a trig- pustules; however, impression smears from both the ger for pemphigus or a potential sequella of an incompletely skin and under the surface of a teased crust will managed chronic inflammatory condition. often be rewarding. Single or rafts of acantholytic cells that are 10–20 times the size of surrounding neutrophils can be found on cytologic evaluation using a Diff-Quik stain (Fig. 13). Characteristi- cally, there is little to no evidence of bacteria, and neutrophils/eosinophils have a healthy appearance (no evidence of toxic changes). Based on these find- ings, multiple skin biopsies should be taken to con- firm the diagnosis. Primary vesicles or pustules, if present, are ideal, and crusted sites are the next best choice for multiple biopsies. Surgical prepara- tion of biopsy sites is not recommended, because the crusts may contain the acantholytic cells necessary for diagnosis. Dermatopathologic findings include subcorneal and/or intraepidermal pustules, spanning multiple hair follicles associated with marked acanthol- ysis, neutrophils, and occasionally, eosinophils. As Trichophyton equinum may mimic the clinical and his- Fig. 6. Crust and alopecia are more commonly found than - tological appearance of pemphigus (crusts and acantho- tules in cases of equine pemphigus. These secondary lesions are lytic cells), fungal stains should be performed on all 10 still useful diagnostic samples for either cytology and/or histopa- biopsies suggestive of pemphigus. Immunohistochemi- thology. cal staining has taken precedence over immunofluores-

494 2006 ր Vol. 52 ր AAEP PROCEEDINGS IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY

Fig. 8. Fig. 9.

cence because of the ability of the former method to ● detect autoantibodies within formalin fixed tissues (e.g., Dexamethasone at an induction dose of 0.02– immunoperoxidase) rather than the need for special han- 0.1 mg/kg/day PO or IV for 7–10 days and then 1 tapering to 0.01–0.02 mg/kg, q 48–72 h. dling of skin samples for direct immunofluorescence. ● The use of immunoprecipitation has been reported in one Prednisolone at 1.5–2.5 mg/kg/day for a 7–10 day period and then tapering over several horse with paraneoplastic pemphigus.5 This technol- ogy is currently available for use in human dermatology weeks to a maintenance dose of 0.5–1 mg/kg, q to confirm the diagnosis and act as a prognosticating tool 48 h. This is preferred if low albumin is detected.6 when evaluating response to therapy. Species specific ● tests are being investigated for the dog and hopefully, for Pentoxifylline at 8–10 mg/kg, 2–3 times/day the horse in the near future.4 and then tapering after steroids have been minimized. ● Azathioprine at 2–3 mg/kg, q 24 h, PO for 3–4 6. Treatment wk and then tapering to every other day. There- Before starting therapy, baseline and follow-up fore, low (1–7%) bioavailability can be costly to bloodwork (CBC and biochemical profile) are rec- maintain.11,12 ommended to monitor the effect of the immuno- ● Injectable gold salts: aurothioglucosea (no suppressive regimen. Multimodal therapy is longer available) or aurothiomalate.b Test often necessary for the treatment of pemphigus in doses of 20 and 50 mg at weekly intervals. If horses and includes the following treatment. no abnormal reactions, 1 mg/kg, IM weekly for 6–12 wk and then tapering to every 2- to 3-wk ● Essential fatty acids: DermCaps 100s, 1 - injections until weaned off entirely. This is sule/50–100 kg, q 12 h. often used in conjunction with steroids during ● Vitamin E: 13 IU/kg/day. the initial induction phase. ● Decreased exposure to sun (photoaggravated ● Monitor CBC for bone marrow suppression disorder). (), drug reactions (eosino- ● High doses of corticosteroids. philia), and glomerulonephritis (proteinuria).

AAEP PROCEEDINGS ր Vol. 52 ր 2006 495 IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY

Fig. 12.

hepatopathies and reported laminitis when using glucocorticoids, bone marrow suppression, and adverse drug reactions with adjunctive immunosup- pressive therapy.12,13 Typically, an initial re- sponse is noted within 7–14 days, and then medication can be tapered 20% every 1–2 wk based on individual responses. Young horses have an excellent prognosis for remission and little chance Fig. 10. of relapse, whereas mature horses tend to have a less favorable prognosis (46%); typically, lifelong therapy is necessary for control of the condi- tion.1,6,7 If a trigger factor can be identified and eliminated, therapy should be tapered and poten- ● Eliminate inciting factor (i.e., tumor extirpa- tially discontinued. tion in paraneoplastic pemphigus).

7. Prognosis Management in horses may take weeks or months to control. It is not without complications including

Fig. 13. Cytology from crust of an equine pemphigus foliaceus case shows acantholytic cells 10–20 times the size of surrounding neutrophils, and deep blue staining cytoplasm, and a central nucleus. Note that there is no evidence of bacteria, and neutro- phils/eosinophils have a healthy appearance (no evidence of toxic Fig. 11. changes).

496 2006 ր Vol. 52 ր AAEP PROCEEDINGS IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY References and Footnotes in the anchoring filaments that connect the base- 1. Scott DW, Miller WH. Pemphigus foliaceus. In: Equine ment membrane to filaments in the superficial der- dermatology. Philadelphia: W.B. Saunders, 2003;480–492. mis.2 A laminin-5 defect has been shown in 2. Johnson ME, Scott DW, Manning TO. A case of pemphigus Belgians and in two French draft breeds (Trait Bre- foliaceus in the horse. Equine Pract 1981;3(2):40–45. 3. Jordon RE. Pemphigus. In: Fitzpatrick TB, Eisen AZ, ton and Trait Comtois); the mutation is a cytosine 5–7 Wolff K, eds. Dermatology in general medicine, 2nd ed. New insertion in exon 10 of the LAMC2 gene. Be- York: McGraw-Hill, 1979;310–317. cause of this knowledge, the Veterinary Genetics 4. Iwasaki T, Shimizu M, Obata H, et al. Detection of canine Laboratory at the University of California at Davis pemphigus foliaceus autoantigen by immunoblotting. Vet Immunol Immunopathol 1997;59:1–10. offers a diagnostic test to determine carrier status 5. Williams MA, Dowling PM, Angarano DW, et al. Paraneo- (available online at www.vgl.ucdavis.edu/service/ plastic bullous stomatitis in a horse. J Am Vet Med Assoc horse/index.html) in Belgian Draft horses and re- 1995;207:331–334. lated breeds. 6. Vandenabeele SIJ, White SD, Affolter VK, et al. Pemphigus Clinical presentation and the age of the foal are foliaceus in the horse: retrospective study of 20 cases. Vet Dermatol 2004;15:381–388. highly suggestive of the diagnosis. Histology and 7. Zabel S, Mueller RS, Fieseler KV, et al. Review of 15 cases ideally, electron microscopy are required to con- of pemphigus foliaceus in horses and a survey of the litera- firm the diagnosis. There is no known treatment, ture. Vet Rec 2005;157:505–509. and affected horses, as well as the sires and dams 8. Stannard AA. Stannard’s Illustrated Equine Dermatology Notes. Immunologic Diseases. 2000;11(3):163–178. of affected horses, should not be bred; the mode of 9. White SD, Carlotti DN, Pin D, et al. Putative drug-related inheritance is autosomal recessive. pemphigus foliaceus in four dogs. Vet Dermatol 2002;13: This disease differs from epitheliogenesis imper- 195–202. fecta (see below). At first, EB does not present 10. Scott DW. Marked acantholysis associated with dermato- large areas of the skin are devoid of , but phytosis due to Trichophyton equinum in two horses. Vet Dermatol 1994;5:105–110. rather, the skin is later lost because of the fibril 11. White SD, Maxwell LK, Szabo NJ. Pharmacokinetics of aza- defect. thioprine following single-dose intravenous and oral admin- Epitheliogenesis imperfecta (aplasia cutis) is an istration and effects of azathioprine following chronic oral inherited, congenital discontinuity of squamous ep- administration in horses. Am J Vet Res 2005;66:1578–1583. 12. White SD, Rosychuk RAW, Outerbridge CA, et al. Thiopu- ithelium. It is thought to be an autosomal reces- rine methyltransferase in red blood cells of dogs, cats, and sive trait, and it has been reported in several breeds. horses. J Vet Int Med 2000;14:499–502. Lesions are most common on the limbs, head, and 13. Eyre P, Elmes PJ, Strickland S. -potentiated . Hooves may slough in severe cases. vascular responses of the equine digit: a possible pharma- Clinical presentation is usually diagnostic.8 In cologic basis for laminitis. Am J Vet Res 1979;40:135–138. moderately to severely affected animals, the disease aSolgonal, Schering, Kenilworth, NJ 07033. is fatal within a few days, because the foal usually bMyochrysine, Merck, Whitehouse Station, NJ 08889. dies of septicemia or other developmental abnormal- ities. Mildly affected areas may heal by scar for- Hereditary Diseases mation. More recent reports would suggest that some of these horses with epitheliogenisis imper- Stephen D. White, DVM, Diplomate ACVD fecta (Saddlebreds) may, in fact, have a condition similar to the junctional EB common in Belgian 1. Introduction foals.9–11 (EB) includes a number of Hereditary equine regional dermal asthenia diseases typified in humans by the common finding (HERDA; “hyperelastosis cutis”) is a disease that of formation after minor trauma. Most occurs early in life in horses. Most affected horses forms are congenital and apparent soon after birth. are Quarter Horses, but registered Paint Horses and In animals and humans, subsets of EB are classified Appaloosas with Quarter Horse lineage have been by the histologic location of the blister or cleft. afflicted with this disease.12,13 Many of the Quar- These subtypes (and respective cleft locations) are ter Horses are from high-quality cutting lines. termed EB simplex (basal cell layer of the epider- The disease (or something very similar) has also mis), junctional EB (intralamina lucida or basal cell been reported in a cross-bred Arabian mare, a Thor- layer), and dystrophic EB (sublamina densa). oughbred gelding, a Hanoverian foal, and a Haf- Junctional EB has been reported in Belgian foals flinger horse.14–17 of both sexes as well as other breeds and a don- The working hypothesis is that these horses have key.1–4 Lesions are usually noted within 3 days of a defect in their collagen fibers or in the way those birth and include multiple asymmetrical irregular fibers are structurally organized in the mid to deep skin erosions and ulcers that are often encrusted. dermis. Typically, these areas are over the back Lesions may be especially prominent around the and sides of the neck (Fig. 1). The skin in these coronary bands (causing the hoof to crack and areas may seem to be easily torn or stretched, and it slough) and on the oral, anal, and genital mucosa. often develops seromas and hematomas (“” Histology and ultrastructural findings point to a filled with either serum or blood) (Fig. 2). Healing cleft in the intralamina lucida of the basement mem- per se is usually adequate but often leaves rather brane zone. This is presumably caused by a defect unsightly scars. Diagnosis is often based on the

AAEP PROCEEDINGS ր Vol. 52 ր 2006 497 IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY

Fig. 1. Stallion with hereditary equine regional dermal asthenia (HERDA).

clinical signs alone; histologic findings are some- As with many genetic diseases, there is no effective times subtle, but “clumped” or poorly organized col- treatment or cure, but some of these horses have lagen fibers below the level of the hair follicles may been maintained as “pasture pets.” be seen. A zone of mid- to deep-dermal separation This disease follows an autosomal recessive mode has been reported in two horses, and it has been of inheritance; therefore, for the foal to be affected, present in some of the biopsy samples that the author both the sire and the dam must carry the gene, and has seen.13,18 “Poorly oriented” collagen fibers are if they were bred again, there would be ϳ25% sometimes seen on electron microscopy. There is no chance that the next foal would also be affected.19 blood test to confirm the disease. At the present time, there is no test available to This condition is almost certainly present at birth; verify carriers. Obviously, clinically affected however, it is often not noticed until ϳ2yrofage horses with the disease should be removed from when horses start being trained with tack, and the breeding programs. friction/trauma of this induces the typical lesions. Progressive chronic is the tentative term for a condition seen in Shires, Clydesdales, and Belgians. It is characterized by progressive swell- ing, hyperkeratosis (thickening), and fibrosis (hard- ening) of the skin on the lower legs. This chronic progressive disease starts at an early age, progresses throughout the life of the horse, and of- ten ends in disfigurement and disability of the limbs. Inevitably, this condition leads to the horse’s pre- mature death. In the Belgian , it has reduced the average life expectancy of a stallion from 20 to 6 yr. The pathologic changes and clinical signs closely resemble a condition known in humans as chronic lymphedema or verrucosa. The lower leg swelling is caused by abnormal func- tioning of the lymphatic system in the skin, which results in chronic lymphedema (swelling), fibrosis, a compromised immune system, and subsequent sec- ondary infections of the skin. Based on prelimi- Fig. 2. Dorsum of filly with HERDA. nary research, it seems that a similar pathogenic

498 2006 ր Vol. 52 ր AAEP PROCEEDINGS IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY mechanism is involved in the disease that affects scribed as “golf ball” or even “baseball” in size. these specific draft horse breeds. Both skin folds and nodules first develop in the back The clinical signs of this disease are highly vari- of the pastern area. With progression, they may able. The earliest lesions are characterized by skin extend and encircle the entire lower leg. The nod- thickening and crusting; both are often visible only ules become a mechanical problem, because they after clipping the long feathering. Secondary infec- interfere with free movement and are frequently tions develop very easily in these horse’s legs and injured during exercise. This disease often usually consist of either chorioptic or bacte- progresses to include massive secondary infections rial infections. Both dark and white skin on the that produce copious amounts of foul-smelling exu- lower legs are equally affected. These lesions are dates, generalized illness, debilitation, and even consistent with pastern dermatitis, which is cer- death.20,21 tainly seen in other breeds. In Shires, Clydesdales, In a recent report on what may be the same con- and Belgians, however, these lesions do not respond dition in several draft breeds, the authors found a well to therapy. perivascular dermatitis dominated by T lympho- As the disease progresses, 1–2 thick skin folds cytes with an increase in major histocompatibility and sometimes multiple small, well-demarcated complex (MHC) class IIϪpositive dendritic-like ulcerations develop predominantly in the rear of cells. Immunohistochemical labeling for cytokera- the pastern region. The ulcerations are covered tins (CK) 5/6, CK10, and CK14 indicated a change in with adherent crusts. Manual removal of the their expression pattern. This correlated with the crusts and even movement during exercise results degree of epidermal hyperplasia, indicating abnor- in bleeding. These small sores may seem to re- mal differentiation of . There was a spond initially to various topical medications, but statistically significant correlation between the they often reverse course, only to progress in se- severity of skin lesions and several other factors verity and multiply in number. Small lesions including increasing age, increasing cannon circum- tend to coalesce into larger and more intractable ference, prominence of anatomical structures such (resistant to cure) areas of skin ulceration. Over as fetlock tufts of hairs, ergots, and chestnuts, and time, the lesions extend up the leg, often affecting bulges in the fetlock region.22 the skin as high as the knees or hocks. These lesions are, at the very least, irritating and both- ersome to the horses and at times, can be quite References painful. Severely affected individuals often ex- 1. Frame SR, Harrington DD, Fessler J, et al. Hereditary junc- hibit generalized swelling in all four legs. tional mechanobulluous disease in a foal. J Am Vet Med This condition is thought to be primarily a lymph- Assoc 1988;193:1420–1424. 2. Johnson GC, Kohn CW, Johnson CW, et al. Ultrastructure system disease, and the pastern dermatitis in these of junctional epidermolysis bullosa in Belgian foals. J Comp draft horses is a secondary result caused by the Pathol 1988;98:331–336. body’s inability to properly supply fluids and oxygen- 3. Kohn CW, Johnson GC, Garry F, et al. Mechanobullous ate the skin of the lower leg. The lymphatics break disease in two Belgian foals. Equine Vet J 1989;21:297– down over time, and protein-rich fluid leaks into the 301. 4. Sloet van Oldruitenborgh-Oosterbaan M, Boord M. Equine tissues of the lower leg, which results in fibrosis of dermatology workshop. In: Thoday KL, Foil CS, Bond R, the tissues under the skin and thickening of the skin eds., Advances in veterinary dermatology, vol. 4. Oxford, itself. The tissue fibrosis leads to even more block- UK: Blackwell Science, 2002;286–290. age of fluid within the legs, thereby inhibiting 5. Linder KE, Olivry T, Yager JA, et al. Mechanobullous dis- proper circulatory flow. This results in neovascu- ease of Belgian foals resembles lethal (Herlitz) junctional epidermolysis bullosa of humans and is associated with fail- larization; this is a process by which the body devel- ure of laminin-5 assembly. Vet Dermatol 2000;11(Suppl 1): ops new blood vessels in a futile attempt to provide 24. oxygen to its tissues. 6. Spirito F, Charlesworth A, Linder K, et al. Animal models Researchers suspect that a deficiency or abnor- for skin blistering conditions: absence of laminin 5 causes mality in a connective tissue component known as hereditary junctional mechanobullous disease in the Belgian horse. J Invest Dermatol 2002;119:684–691. elastin is the underlying element and perhaps, the 7. Milenkovic D, Chaffaux S, Taourit S, et al. A mutation in cause of the lymphatic degeneration in these horses. the LAMC2 gene causes the Herlitz junctional epidermolysis In affected animals, the lymph vessels and deep bullosa (H-JEB) in two French draft horse breeds. Genet Sel tissues of the skin do not have sufficient amounts or Evol 2003;35:249–256. proper configuration of elastin. The lack of this 8. Crowell WA, Stephenson C, Gosser HS. Epitheliogenesis imperfecta in a foal. J Am Vet Med Assoc 1976;168:56–58. critical tissue element apparently instigates the pro- 9. Dubielzig RR, Wilson JW, Beck KA, et al. Dental dysplasia gression of disease and the chronic progression of and epitheliogenesis imperfecta in a foal. Vet Pathol 1986; clinical signs. 23:325–327. As the condition becomes more chronic, the lower 10. Lieto LD, Swerczek TW, Cothran EG. Equine epitheliogen- leg enlargement becomes permanent, and the swell- esis imperfecta in two American Saddlebred foals is a lamina lucida defect. Vet Pathol 2002;39:576–580. ing is firm on palpation. More thick skin folds and 11. Lieto LD, Cothran EG. The epitheliogenesis imperfecta lo- large, poorly defined, firm nodules develop. The cus maps to equine chromosome 8 in American Saddlebred nodules may become quite large and are often de- horses. Cytogenet Genome Res 2003;102:207–210.

AAEP PROCEEDINGS ր Vol. 52 ր 2006 499 IN-DEPTH: SELECTED TOPICS IN DERMATOLOGY

12. Hardy MH, Fisher KR, Vrablic OE et al. An inherited con- with hyperelastosis cutis in a Quarter Horse. Vet Dermatol nective tissue disease in the horse. Lab Invest 1988;59:253– 2001;12:219–221. 262. 19. Tryon RC, White SD, Famula TR, et al. Inheritance of 13. White SD, Affolter V, Bannasch DL, et al. Hereditary hereditary equine regional dermal asthenia (HERDA) in equine regional dermal asthenia (HERDA; ‘Hyperelastosis the American Quarter Horse. Am J Vet Res 2005;66:437– cutis’) in 50 horses: clinical, histologic and immunohisto- 442. logic findings. Vet Dermatol 2004;15:207–217. 20. de Cock HE, Affolter VK, Wisner ER, et al. Lymphoscinti- 14. Solomons B. Equine cutis hyperelastica. Equine Vet J graphy of draught horses with chronic progressive lympho- 1984;16:541–542. edema. Equine Vet J 2006;38:148–151. 15. Gunson DE, Halliwell RE, Minor RR. Dermal collagen degra- 21. De Cock HE, Affolter VK, Wisner ER, et al. Progressive dation and phagocytosis. Occurrence in a horse with hyperex- tensible fragile skin. Arch Dermatol 1984;120:599–604. swelling, hyperkeratosis, and fibrosis of distal limbs in 16. Witzig P, Suter M, Wild P, et al. Dermatosparaxis in a foal Clydesdales, Shires, and Belgian draft horses, suggestive and a cowϪa rare disease? Schweiz Arch Tierheilkd 1984; of primary lymphedema. Lymphat Res Biol 2003;1:191– 126:589–596. 199. 17. Scott DW, Miller WH Jr. Equine dermatology. St. Louis: 22. Geburek F, Ohnesorge B, Deegen E, et al. Alterations of W.B. Saunders, 2003;640. epidermal proliferation and cytokeratin expression in skin 18. Brounts SH, Rashmir-Raven AM, Black SS. Zonal dermal biopsies from heavy draught horses with chronic pastern separation: a distinctive histopathological lesion associated dermatitis. Vet Dermatol 2005;16:373–384.

500 2006 ր Vol. 52 ր AAEP PROCEEDINGS