Signalment: 2-year-old male castrated Chihuahua beagle mix. Presenting complaint: Areas of alopecia and ulcers/erosions. Figure 1. Figure 2.

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1 Signalment: 2-year-old male castrated Chihuahua beagle mix. Presenting complaint: Areas of alopecia and ulcers/erosions Figure 1. Figure 2.

2 Figure 3. Figure 4. Figure 5.

3 Figure 6. Figure 7. Clinical history: The patient presented for evaluation of sudden worsening of skin lesions over a one week period. An initial area of alopecia was noted on the top of the patient s head and right hind limb, and mild crust on his ear tips starting 2 months ago. At that time skin biopsies were submitted by the referring veterinarian and described a mild eosinophilic perivascular dermatitis. The patient was initially treated with cefpodoxime with no resolution. The patient receives fluralaner (Bravecto ) for flea/tick control and ivermectin (Heartgard ) for heartworm prevention. The patient eats beef flavored Purina small breed, although he was recently switched to this from Beneful one to two months ago. The patient lives with 1 other dog with no skin lesions. The patient s vaccination status [rabies and DA2PP (distemper virus, adenovirus, parainfluenza virus, and parvovirus) is current.

4 Question: What is the most likely cause/etiology? Answer: A) Food allergy B) Leishmania C) Vaccine reaction (Rabies, Distemper) D) Autoimmune E) Cold-agglutinin disease Clinical presentation: Over the dorsal aspect of the calvarium is an approximately 4-5 cm round area of alopecia and hyperpigmentation. Alopecia with mild erosion and crusting is present at mucocutaneous junctions (especially along lip commissures). Periocular regions are swollen, with hypotrichosis and mild moist erosion with crusting. Along the dorsal muzzle is hyperpigmentation with crust. Alar folds are slightly crusted with hypopigmentation. Ventrally along the external nares on the left side is an area of hypopigmentation that appears slightly swollen. Bilaterally at distal tip of concave pinna are approximately 2-3 cm symmetrical full thickness ulcers with surrounding hyperpigmentation. Pinnal margins have mild crust/scale. The dorsal pedal surface has patchy alopecia with mild scale and underlying hyperpigmentation. Hocks and elbows are alopecic hyperpigmented with fine scale. On the ventral aspect of paw pads are fine pinpoint to linear indurated areas of scale and hypopigmentation. Along the right lateral thigh there is an area of moderate scale and patchy hyperpigmentation. Histopathologic description: Four samples are examined with a serocellular crust of neutrophils, cell debris and serum. The samples show similar features with a varying degree of inflammation. The least inflamed haired skin sample has features typical of ischemic dermatopathy. Hair follicles are atrophied (some faded), and the dermal collagen and vascular tunics of small capillaries are slightly smudged. There is interstitial mucin deposition, small foci of perivascular hemorrhage, as well as scattered macrophages and neutrophils. The epidermis is mildly hyperplastic, hyperpigmented, and has a cell poor interface change. There is orthokeratotic hyperkeratosis. A second skin sample has these features, along with more prominent acanthosis and a dense neutrophilic infiltrate in the superficial dermis. In the smaller punch biopsies, there is dermoepidermal clefting with ulcers and fibrinosuppurative inflammation. Regionally, the epidermis shows thinning and squamatization with a more prominent hydropic change in the basal layer. The crust contains serum, necrotic granulocytes, bacteria, neutrophils, pigmented fungi, and a portion of an insect.

5 Figure 8. Figure 9. Morphologic diagnosis CELL-POOR INTERFACE DERMATITIS WITH FOLLICULAR ATROPHY (ISCHEMIC DERMATOPATHY) AND SUPERFICIAL NEUTROPHILIC DERMATITIS WITH ULCER AND CRUST Comments: In this case, vaccine-associated generalized ischemic dermatopathy was considered most likely given the history of vaccination 3 months prior and localized lesion at a known vaccine site.

6 Ischemic dermatopathy is a histologic diagnosis that typifies a number of different clinical syndromes with common features and a wide range of possible etiologies. Histologic features, including follicular atrophy, collagen smudging and cell poor interface pattern (with or without clefting of the basement membrane zone) are thought to represent a chronic oxygen deficient state of the affected tissue. A large number of cases demonstrate a mild perivascular to interstitial lymphoplasmacytic dermatitis and more inflamed lesions may be ulcerated with suppurative inflammation. Rarely, vasculitis may be noted, although some cases may have changes consistent with vascular atrophy. Muscle fibers, if present, may be atrophied. (Gross, 2005) Without a complete history and clinical signs, the various syndromes are indistinguishable histologically, thus some effort has been made to group the diseases based on clinical features. Primary ischemic diseases have previously been grouped into five subtypes; Canine familial dermatomyositis (FDM) {see November 2017 COM}, vaccine associated ischemic dermatopathy, generalized idiopathic ischemic dermatopathy, familial cutaneous vasculopathy of the German Shepherd dog, and pinnal margin vasculopathy. (Morris, 2013) The most recognized and studied subtype, canine familial dermatomyositis, has been described in rough collies, Shetland sheepdogs and a group of Beauceron shepherds. While the pathogenesis is not well described, an immune-mediated mechanism is thought to drive the development of disease in genetically susceptible individuals following an environmental trigger. Environmental triggers such as infections, vaccines, drugs, UV exposure and stressful events have been postulated in connection to individual cases. (Hargis, 1992, Wilcock, 1986, Vitale 1999) A few genetic studies have been able to identify susceptible MHC haplotypes in collie and Shetland sheepdogs. Recently two candidate genes were identified, which, along with the corresponding risk MHC haplotypes, confer increases susceptibility to disease. These findings have also shed light on the differences in age of onset, indicating that those individual with more risk alleles have a greater likelihood in developing the disease at a younger age. (Evans, 2017) Unlike humans, compelling evidence for cell mediated or humoral mechanisms has not been demonstrated. (Wahl, 2008) (Hargis, 1986) (Haupt, 1985) Less is known about the other subtypes of ischemic dermatopathy other than a few case reports and clinical anecdotal mantra. Generally, rabies associated ischemic dermatopathy may be focal or generalized. These cases are reported most commonly in young to middle aged small breed dogs, with miniature and toy poodles, Chihuahuas and Yorkshire terriers being the most commonly reported breeds. (Backel, unpublished dated) Alopecia, variably ulcerated or pigmented lesions are found most commonly over a vaccine sites and may generalize to include areas such as the ears, tip of the tail, head and face, pressure points and paw pads. The first case series was published in 1986, outlining focal alopecic and vasculitis in 13 dogs associated with rabies vaccine administration. The report described alopecic lesions that appeared 3-6 months after vaccination in those areas. Ten out of the thirteen cases were miniature poodles. In 3 out of 3 cases tested, rabies-specific fluorescence was identified in blood vessel walls and follicular epithelium indicating a possible involvement of the virus product itself. (Wilcock,

7 1986) A second case series in 1999, described generalized lesions in three small breed dogs who developed more generalized lesions 1-5 months after vaccination. Using an endothelial marker (factor VIII) and immunofluorescence for complement deposition in skeletal muscle, this study demonstrated reduced vascularity and presence of activated complement components in affected skeletal muscle. (Vitale, 1999) Thus, similar to human dermatomyositis a complementmediated mechanism of disease induction is considered most likely. Even less is known about idiopathic generalized ischemic dermatopathy in which an obvious vaccine trigger cannot be identified. Cases may present in a similar manner as described above, except without a history of recent vaccination or a localized vaccine-site lesion. The prognosis of these clinical syndromes is also relatively unknown. In one study the cases responded well to therapy with Pentoxifylline, Vitamin E and in two cases, short courses of prednisone.(vitale, 1999) Anecdotally, some cases are more difficult to manage, requiring many different immunosuppressive agents and sometimes progress despite treatment. A more recent case report described the management of vaccine associated generalized ischemic dermatopathy in which remission was achieved utilizing IVIG, and prednisone, following by a combination Chlorambucil and cyclosporine. (Kim, 2011) Cited works: Evans JM, Noorai RE, Tsai KL, Starr-Moss AN, Hill CM, et al. (2017) Beyond the MHC: A canine model of dermatomyositis shows a complex pattern of genetic risk involving novel loci. PLOS Genetics 13(2): e Wahl JM, Clark LA, Scalli O, et al. Analysis of gene transcript profiling and immunobiology in Shetland sheepdogs with dermatomyositis. Vet Dermatol 2008;19: Hargis AM, Prieur DJ, Haupt KH, et al. Prospective study of familial canine dermatomyositis. Correlation of the severity of dermatomyositis and circulating immune complex levels. Am J Pathol 1986;123: Haupt KH, Prieur DJ, Hargis AM, et al. Familial canine dermatomyositis: clinicopathologic, immunologic, and serologic studies. Am J Vet Res 1985;46: Morris, DO. Ischemic Dermatopathies. Vet Clin North Am Small Anim Pract Jan;43(1): Wilcock BP, Yager JA. Focal cutaneous vasculitis and alopecia at sites of rabies vaccination in dogs. J Am Vet Med Assoc 1986;188:

8 Vitale CB, Gross TL, Magro CM. Vaccine-induced ischemic dermatopathy in the dog. Vet Dermatol 1999;10: Kim HJ, Kang MH, Kim JW, et al. Long-term management of vaccine-induced refractory ischemic dermatopathy in a miniature pinscher puppy. J Vet Med Sci 2011;73: Contributors: Drs. Katherine Backel and Charles Bradley School of Veterinary Medicine, University of Pennsylvania (US)