"HOT" TOPICS FROM THE NORTH AMERICAN VETERINARY DERMATOLOGY FORUM Rod A.W. Rosychuk, DVM, DACVIM

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1 "HOT" TOPICS FROM THE NORTH AMERICAN VETERINARY DERMATOLOGY FORUM Rod A.W. Rosychuk, DVM, DACVIM HIGHLIGHTS The North American Veterinary Dermatology Forum was held in April Hot topics from this forum were often abstracts, sharing cutting edge material. It should be pointed out, however, that information presented in abstract form at such meetings has not undergone peer review, and as such may not appear as it will in its final, published form. The following are data that the author has considered most interesting and clinically applicable. It must be emphasized that the selection of these topics reflects the interest of the author. They only represent a fraction of the excellent information presented at the meeting. Canine Atopy 1. It has been well established that the transcutaneous absorption of allergens plays an important role in the initiation and perpetuation of atopy in dogs. This at least in part helps to explain the distribution of lesions seen in atopic dogs (less haired areas, areas more prone to abrasion [flexural surfaces]). It has also been shown in the past (Inman et al. 2001) that the epidermal lipid barrier is disrupted in nonlesional atopic skin (continuity and thickness of lipid lamellae decreased in nonlesional atopic skin). Hightower et al., in an abstract presented at this meeting, compared transepidermal water loss (TEWL) in beagle dogs sensitized to house dust mites versus normal dogs. Before allergen challenge, increased TEWL was noted in the axillae, antecubital fossa, chin, periocular, pinna, and thorax of atopic, compared to normal dogs. Following allergen exposure, TEWL significantly increased in the axillae, antecubital fossa, groin, pinna, and thorax of atopic dogs versus control dogs. The abstract suggested that atopic dogs have altered barrier function in lesional predilection sites, which is aggravated by allergen exposure. Significance: increases in TEWL again support the presence of a barrier defect in these areas. Clinical significance: Barrier defects could facilitate antigen uptake in these areas. Increased TEWL itself may potentiate pruritus (i.e., dry skin potentiates pruritus). We are now beginning to see the addition of fatty acids (e.g., phytosphingosines in the Sogeval products) in shampoos, conditioners, sprays, and top-spot products to address these defects (i.e., phytosphingosines function as pre-ceramides, with ceramides being one of the important lipids within the skin). 2. Antihistamines are commonly used in the management of canine atopy. Antihistamines and drugs with antihistamine-like activity that have been shown to be of benefit include hydroxyzine, chlorpheniramine, diphenhydramine, clemastine, loratadine, cetirizine, amitriptyline, fexofenadine, cyproheptadine, and doxepin HC. It has been suggested that if multiple different antihistamines are tried in a given individual, there is about a 20 30% chance that one or more may be found to benefit the individual. It is not possible to predict which antihistamine will be of most value to a given individual, and therefore each should be given for a trial period of days. Hydroxyzine is often suggested to be one of the antihistamines more likely to be of benefit in individuals. Hydroxyzine is generally dosed at 2 mg/kg BID or TID. Bizikova et al. presented an abstract in which they showed that when hydroxyzine was given at a dose of 2 mg/kg, there was a very rapid conversion of hydroxyzine to cetirizine (cetirizine concentrations 15 times that of hydroxyzine). The effect of varying increased dosages or frequencies of administration on intradermal histamine wheal formation showed that 2 mg/kg, given BID produced > 80% wheal inhibition and that greater dosages or frequencies of administration did not improve upon this effect. Clinical significance: Dosage of hydroxyzine should be 2 mg/kg BID. The data suggested that the maximal benefit of hydroxyzine administration may actually be due to the effects of its metabolite, cetirizine. Similar work should be done utilizing cetirizine (Zyrtec). Early work with this drug given at a dose of 1mg/kg once daily showed a significant benefit in 18% of individuals. There may be some advantage of giving mg BID. 3. The microflora of the conjunctival sac of normal dogs was compared with that of dogs with atopic dermatitis, but with no evidence of conjunctivitis (Furiani N et al.). Bacteria were isolated from 53.3% of atopic dogs (n = 15) and 14.2% of healthy dogs. In atopic dogs, Staphylococcus spp was predominantly isolated (62.5%), followed by Bacillus spp (25%). Malassezia was isolated in one atopic dog. Cytologic examination revealed the presence of bacteria adhered to epithelial cells in 86.6% of atopic dogs and 14.2% of healthy dogs. Epithelial and inflammatory cells were more numerous in atopic dogs. 313

2 Cyclosporine Cyclosporine is now relatively commonly used in the management of various dermatoses in dogs and cats. In dogs, cyclosporine is most commonly used to treat atopy. The dosage that is used is most commonly for this purpose is 5 mg/kg/day. Cyclosporine has also been reported to be effective in the treatment of autoimmune/immune-mediated diseases, including vesicular cutaneous lupus erythematosus, pemphigus foliaceus, and erythema multiforme and other diseases wherein the pathogenesis is unclear, including sebaceous adenitis, perianal fistulas, sterile pyogranulomatous dermatitis, sterile panniculitis, and reactive histiocytosis. Cyclosporine has also been used to prevent renal transplant rejection. In the treatment of autoimmune/immune-mediated diseases, the target trough blood concentrations of cyclosporine are between ng/ml. The attainment of these concentrations often requires higher dosages of cyclosporine (e.g., 5 10 mg/kg/day or 3 5 mg/kg BID). There was a report (Mauldin et al.)of 5 dogs with exfoliative cutaneous lupus erythematosus that were treated with mg/kg/day cyclosporine for 4.5 months to 2 years (maximum). Four of these dogs also received 5 7 mg/kg/day ketoconazole. Cyclosporine decreased joint pain and stiffness and provided temporary improvement of skin lesions (mainly decreased erythema) but did not halt disease progression. No side effects were seen (monthly CBC/biochemistry screens). At this meeting, emphasis was placed on some of the complications associated with cyclosporine administration. At atopy dosages the most common side effects involved gastrointestinal upsets (e.g., vomiting, diarrhea, inappetence). Other side effects that have been noted rarely include hyperglycemia (at higher dosage regimens?), asymptomatic hepatopathy (increased ALT, etc.), leucopenia, thrombocytopenia, tremors (generalized or facial), ataxia and intention tremors, disorientation, and seizures. Certain cutaneous neoplasias have been anecdotally noted to worsen on cyclosporine therapy (e.g., histiocytomas, sebaceous adenomas). Although individuals on cyclosporine have been noted to develop more serious neoplasias (e.g., hepatic carcinoma, gastric carcinoma, hepatic hemangiosarcoma, pulmonary adenocarcinoma, lymphoma, cutaneous epitheliotropic lymphoma), no clear cause and effect association with these tumors could be made. Gingival hyperplasia is an uncommon adverse effect of cyclosporine. In many instances it does not seem to bother the dog. Dental hygiene (e.g., brushing, rinses) may be of some benefit. Reducing the dosage of cyclosporine (i.e., reduce the daily dose or go to every other day dose) is noted to produce variable benefits. Stopping the cyclosporine will often result in improvement/normalization. Some individuals may be able to start back on the cyclosporine without having the problem recur. Azithromycin has been used to successfully manage human transplant patients with cyclosporine-induced gingival hyperplasia when the cyclosporine cannot be discontinued. There was a case report (Diesel et al.) of a 4-year FS golden retriever successfully treated for atopy with a generic cyclosporine at a dosage of 3.8 mg/kg once daily and ketoconazole at 3.8 mg/kg once daily for 9 months. The patient developed severe gingival hyperplasia. Successful therapy involved reducing the frequency of cyclosporine administration to every other day and treating with azithromycin (10mg/kg once daily for 6 weeks). This therapy resulted in an almost complete resolution of the gingival hyperplasia. Of 17 dogs that received renal transplants at UC Davis (Sykes), 29% developed infectious complications. Bacterial infections accounted for the vast majority of infections. Four dogs had moderate to severe bacterial pyoderma. Disseminated papillomatosis was reported in 2 dogs. In dogs treated for immune-mediated disease, cutaneous infectious complications included cryptococcosis, phaeohyphomycosis (Curvularia, Alternaria), oral papillomatosis, toxoplasmosis, nocardiosis, and disseminated aspergillosis (Sykes). In cats, cyclosporine is again used most commonly to treat atopy (dosage of 5 10 mg/kg/day). It has also been used to treat immune-mediated skin disease (primarily pemphigus foliaceus). It has been used routinely to treat renal transplant patients. In a review of 169 feline renal transplant recipients that had been treated with both prednisone and cyclosporine, 25% developed infectious complications (Sykes). Bacterial infections were most common, accounting for 53% of infections, followed by viral infections (28%), fungal infections (13%), and protozoal infections, including toxoplasma and Giardia (6%). Of the cats with bacterial infections, 25% had cutaneous infections associated with feeding tubes. Infections with mycobacteria, Nocardia, and Actinomyces were noted. Six cats developed fungal infections (cryptococcosis, dermatophytosis, cutaneous and disseminated candidiasis, and disseminated cladosporiosis). Reactivation of upper respiratory viral infections and toxoplasmosis tended to occur soon after surgery. Fungal infections tended to occur much later. The odds of developing infections increased sixfold in cats that developed diabetes mellitus. 314

3 Summary: Especially at more aggressive dosages, we must be aware of the possibility of encountering these side effects. Exfoliative Cutaneous Lupus Erythematosus This is a disease that affects German shorthaired pointers, with an age of onset < 1 year. It has an autosomal recessive mode of inheritance. The disease is characterized by heavy scaling (follicular casting) over the head and outer pinna and can become generalized. The disease is also characterized by focal areas of adherent crusting and focal areas of erosion and ulceration. Biopsies from affected skin have lupus-like histopathology. Concurrent evidence of sebaceous adenitis may be present. Affected individuals may have blood dyscrasias or joint disease. The disease is widely recognized to respond poorly to a number of anti-inflammatory/immunosuppressive drugs (glucocorticoids, doxycycline or tetracycline and niacinamide, fatty acids). There was a report that was a testament to these previous findings. Five dogs received oral cyclosporine at mg/kg/24hr for years. In 4 dogs, the drug was combined with ketoconazole (5 7 mg/kg/24hrs). Cyclosporine decreased joint pain and stiffness and provided temporary improvement of skin lesions, but did not halt disease progression. Three dogs received hydroxychloroquine (10 mg/kg/24hrs for 6 weeks to 7.5 months). Although no side effects were seen (weekly CBC, serum biochemistry screens, normal EKG), this therapy only mildly improved clinical signs. Four dogs were euthanized between 1 and 3 years of age due to disease progression. Two dogs received a commercial human monoclonal TNF-alpha antagonist adalimumab (Humira, Abbott Labs) at 0.5 mg/kg q wks sc for 12 weeks. Although no side effects were noted, only a temporary improvement was seen in both skin lesions and lameness. Canine Bacterial Pyoderma Methicillin Resistant Staphylococci Staphylococci are recognized as the most common bacteria associated with bacterial pyoderma in the dog. The most common of the group is coagulase positive Staphylococcus intermedius. Dr. D. Morris provided a very thorough, state of the art review of methicillin resistance in staphylococci and its implications for veterinary dermatology. He pointed out that the vast majority of what we have called Staphylococcus intermedius to date are actually a genotypically separate bacteria called Staphylococcus pseudintermedius (gene sequence based methods required to differentiate) (Faires et al ACVIM Forum Abstracts). Other coagulase positive bacteria that are less commonly encountered include Staphylococcus aureus and Staphylococcus schleiferi coagulans. Coagulase negative staph that can also be of significance include Staphylococcus epidermidis and Staphylococcus schleiferi schleiferi. With respect to methicillin resistant staphylococcus aureus (MRSA), Dr. Morris pointed out that communityacquired MRSA are beginning to displace the traditional hospital-acquired MRSA and that hospital strains have begun to spread into the community, in humans. With regard to veterinary health care workers, prevalence studies have been conducted in small surveys. Isolates of MRSA strains from pets and veterinary personnel have usually been indistinguishable. At the 2005 ACVIM Forum in Baltimore, 417 attendees were nasal swabbed. Of these 6.5% were MRSA-positive; of these 15.6% of persons in large animal practices, 4.4% of persons in small animal practices, and 0% in industry or research were colonized. Dr. Morris reviewed individual case reports and small case series that suggest transmission of MRSA from humans to pet animals, and less commonly MRSA-infected or colonized animals that have passed the organism back to people, in some cases wherein the pet was the reservoir for recurrent infections in in contact humans. Resistance rates for MRSA were high for fluoroquinolones (90%) and clindamycin (72%), but low for trimethoprim-sulfa (3%). Less is known about methicillin resistant staph intermedius (MRSI) and schleiferi (MRSS). A previous study showed that MRSS and MRSI isolates were commonly associated with superficial skin and ear canal infections in dogs and cats and commonly expressed multi-drug resistance (beyond beta lactams). In Dr. Morris s lab, susceptibility to the fluoroquinolones, marbofloxcin, and enrofloxacin was significantly greater in MRSS than MRSA. The frequency of antimicrobial resistance was highest for MRSA, followed by MRSI. MRSS maintained susceptibility (>50%) to the greatest number of non-beta lactam antibiotics. Chloramphenicol was noted to be one of the most consistently effective antibiotics for the treatment of MRSI. In an attempt to establish the prevalence of MR staph, Dr. Morris reviewed a recent publication in which both normal dogs (50) and dogs with inflammatory skin disease (59) were swabbed for culture (nasal mucosa, oral mucosa, caudodorsal head, groin, and anal ring). 55/59 dogs with inflammatory skin disease showed MR staph. 83.6% were Staph. intermedius (MR in 8.7%), 9.1% were Staph. aureus (MR in 20%), Staph. schleiferi (coag. +) in 315

4 7.3% (MR in 25%), and 9.1 % Staph. schleiferi (coag. ve) (MR -20%). MR staph were cultured from 35/50 normal dogs: 97.1% were Staph. intermedius (MR in 2.9%), 20% were Staph. aureus (14.3% MR), and 2.9% were Staph. schleiferi (coag. +) (none were MR). Dr. Morris also reviewed the Society for Healthcare Epidermiology of America guidelines (2003) for preventing nosocomial transmission of multiple drug resistant strains of MRSA. The document stresses the importance of active surveillance cultures coupled with barrier nursing (hand hygiene, favoring the use of gloves with gowns over the use of gloves alone) and antibiotic stewardship and decolonization/suppression of colonized patients. He pointed out very useful recommendations that are available at the website of the Centers for Disease Control and Prevention (ww.cdc.gov) and are easily extrapolated to pets, and of the British Small Animal Veterinary Association, which has posted guidelines at Techniques for Culturing the Skin Validated collection techniques for culturing from the skin are noted to include sampling from unbroken pustules/bullae, dry swabs of epidermal collarettes, and biopsy. Vaughn et al. presented an abstract wherein they looked at dependability of culturing from adherent crusts versus skin biopsies. There was a strong correlation between the two. Biopsies, however, did provide heavier growth. Microbiologic and Histopathologic Features of Canine Acral Lick Dermatitis (ALD) Shumaker et al. looked at 31 ALD lesions. Cytology and superficial cultures were compared to biopsies for culture. Bacteria were isolated from 30/31 cases. Of these 57% were staphylococcus intermedius (10% MRSI), the rest were other staph organisms. 24% of all isolates were MRS; 14.3% were resistant to > 3 drug classes. Cytology and superficial cultures did not correlate with deep cultures. It was surmised that ALD warrants deep bacterial cultures as the majority of cases yielded positive growth of bacteria often resistant to empirical drugs and different from superficial cultures. Cefovecin This meeting marked the official launch of the new, injectable cephalosporin Cefovecin (Convenia, Pfizer) to the Veterinary Dermatologist Community (although it had already been launched nationally). The product has been shown to be similar in effect to other cephalosporins (specifically cefadroxil), it is given by subcutaneous injection every 2 weeks, and it is labeled for 2 consecutive injections (although it is labeled for 4 injections in Europe). There was good feedback from European dermatologists who had used the product for some time (in cats; it is difficult to pill dogs; because of owner s desire to reduce the amount of oral medication being given, etc.). Efficacy was as good as or perhaps even slightly better than with cephalexin (perhaps because of compliance issues). No significant side effects had been noted to date. Etiopathogenesis of Alopecia X Alopecia X (hair cycle arrest) is a well-recognized syndrome involving nonpruritic, symmetric alopecia affecting the trunk and tail and sparing the head and distal extremities. Its pathogenesis is not clear. It has been suggested that the alopecia may be mediated by low grade hyperadrenocorticism; adrenal sex hormone imbalance may be estrogen receptor mediated or may involve some other follicular dysfunction. In any case, hair follicles essentially remain in catagen or early telogen and do not move in to anagen, or the growing phase of the hair cycle. In order to better understand the importance of estrogen receptors in the control of transition from telogen to anage, Kirzeder et al. presented an abstract in which they looked at estrogen receptor alpha staining in a variety of breeds and skin conditions. The influence of inflammation and coat type on the presence and intensity of estrogen receptor alpha staining was evaluated. There were no statistically significant differences in estrogen receptor staining when comparing inflammatory to noninflammatory biopsies or biopsies from different coat types. It was surmised that the estrogen receptor alone is unlikely the controlling factor for the transition from telogen to anagen. Effects of Light Exposure and Temperature Variations on Time to Growth of Dermatophytes Using Commercial Fungal Culture Media Verbrugge et al. looked at the effect of temperature on sporulation of Microsporum canis, M. gypseum, and Trichophyton spp using commercial fungal culture plates and the effect of light exposure on M. canis growth. Six commercial dermatophyte fungal culture plates were incubated at 25C (n = 5 plates) or 30C (n = 5 plates). Modified Mycosel (BD Diagnostics) were inoculated with M. canis and incubated at 25 C under 4 light conditions (n = 10 plates each): 24 hours, 12 hours, routine laboratory lighting (control), and 24 hours of darkness. Mean time to 316

5 sporulation was days. Consistent sporulation was found at 5 days in all plates. Colony growth and sporulation were the same for all light exposures. In this study, days to growth and sporulation were not influenced by light exposure or temperature. 317