Oclacitinib 10 years later: lessons learned and directions for the future.

Oclacitinib was approved in the United States 10 years ago for the management of atopic dermatitis (AD) and allergic skin disease in dogs. Many studies and case reports have been published in the past 10 years on the efficacy and safety of this medication, both at labeled doses to treat allergic dogs and off label to treat other diseases and given to other species. Concerns and confusion have occurred for both clinicians and owners regarding the long-term safety of this drug. The purpose of this review is to present the current knowledge on the efficacy, speed of action, effects on the immune system, and clinical safety of oclacitinib, based on evidence and published literature. We also aim to summarize the lessons learned in the past 10 years and to propose directions for the future.

Independent COL5A1 Variants in Cats with Ehlers-Danlos Syndrome.

We investigated four cats with similar clinical skin-related signs strongly suggestive of Ehlers-Danlos syndrome (EDS). Cases no. 1 and 4 were unrelated and the remaining two cases, no. 2 and 3, were reportedly siblings. Histopathological changes were characterized by severely altered dermal collagen fibers. Transmission electron microscopy in one case demonstrated abnormalities in the collagen fibril organization and structure. The genomes of the two unrelated affected cats and one of the affected siblings were sequenced and individually compared to 54 feline control genomes. We searched for private protein changing variants in known human EDS candidate genes and identified three independent heterozygous COL5A1 variants. COL5A1 is a well-characterized candidate gene for classical EDS. It encodes the proα1 chain of type V collagen, which is needed for correct collagen fibril formation and the integrity of the skin. The identified variants in COL5A1 are c.112_118+15del or r.spl?, c.3514A>T or p.(Lys1172*), and c.3066del or p.(Gly1023Valfs*50) for cases no. 1, 2&3, and 4, respectively. They presumably all lead to nonsense-mediated mRNA decay, which results in haploinsufficiency of COL5A1 and causes the alterations of the connective tissue. The whole genome sequencing approach used in this study enables a refinement of the diagnosis for the affected cats as classical EDS. It further illustrates the potential of such experiments as a precision medicine approach in animals with inherited diseases.

Efficacy of a quaternary ammonium compound in reducing coagulase-positive staphylococcal colony counts in veterinary dermatology exam rooms following two cleaning instruction protocols.

BACKGROUND: Nosocomial meticillin-resistant (MR) staphylococcal infections are of global concern. Veterinary dermatology exam room surfaces may be a reservoir given the commonness of staphylococcal pyoderma. HYPOTHESIS/OBJECTIVES: First, efficacy of exam room surface decontamination using a quaternary ammonium compound was assessed after use of two different cleaning instruction protocols. Second, coagulase-positive staphylococcal (CoPS) colony counts were assessed after use of rooms by dogs with pyoderma, and then after cleaning and disinfection. METHODS AND MATERIALS: In Part I, 10 room surfaces were tagged with a discreet fluorescent dye, Glo Germ, to assess the efficacy of surface cleaning between two Virex II 256-based cleaning protocols. In Part II, CoPS colonies were quantified via 3M Staph Express System. Ten standardised room surfaces were sampled after use by a dog with staphylococcal pyoderma, and immediately after a detailed cleaning and disinfection protocol. RESULTS: A total of 24 of 100 and 81 of 100 surfaces were completely cleaned by the general and detailed protocols, respectively. The mean number of surfaces adequately cleaned was higher with the detailed protocol (P = 0.003). The detailed protocol reduced CoPS colony counts of eight surfaces (P < 0.01), and not chairs (P = 0.055). No CoPS were isolated from the exam table under a table mat. CONCLUSIONS AND CLINICAL RELEVANCE: Detailed exam room cleaning and disinfection protocols are recommended to minimise contamination of veterinary exam room surfaces with staphylococci. The appropriate disinfection of chairs necessitates further study.

Probable cutaneous adverse drug reaction due to a cannabidiol-containing hemp oil product in a dog.

BACKGROUND: Cannabidiol (CBD) in hemp oil has become a widely used product in veterinary medicine. To date, there have been no reports of cutaneous adverse events associated with CBD-containing oil in the veterinary literature. CLINICAL SUMMARY: A 4-year-old castrated male Labrador retriever presented with pad sloughing and rapidly progressive cutaneous and mucosal ulceration within five days of administering an oral CBD oil product. Histopathological findings in combination with cutaneous signs were consistent with Stevens-Johnson syndrome. All lesions completely resolved after discontinuation of the hemp oil in addition to a 12 day course of cephalexin and prednisone. Given the lack of alternative causes including other medications, an adverse drug event was deemed probable according to the Naranjo algorithm. CONCLUSIONS AND CLINICAL IMPORTANCE: To the best of the authors' knowledge, this is the first report of suspected cutaneous adverse drug reaction to a CBD-containing hemp oil product.

Efficacy of three disinfectant formulations and a hydrogen peroxide/silver fogging system on surfaces experimentally inoculated with meticillin-resistant Staphylococcus pseudintermedius.

BACKGROUND: Effective environmental disinfection is necessary to prevent nosocomial infections from meticillin-resistant Staphylococcus pseudintermedius (MRSP). However, there are currently no commercial disinfectant sprays or fogging systems with label claims against MRSP. HYPOTHESIS/OBJECTIVES: To evaluate the efficacy of a quaternary ammonium product (QAC), an accelerated hydrogen peroxide product (AHP), a hydrogen peroxide and silver product (HAL), and a hydrogen peroxide and silver fogging system (FOG) against MRSP. METHODS AND MATERIALS: Sterile plastic surfaces inoculated with MRSP were treated with 200 µL of QAC, AHP or HAL for the recommended contact times. For FOG, inoculated samples were placed in eight positions within a sealed room before fogging for the recommended contact time. Post-treatment bacterial counts were compared to untreated positive controls. Sterile uninoculated surfaces served as negative controls. RESULTS: Least-squares mean reduction (log10 ) in colony forming units (cfu) was 3.55 log10 for QAC (P < 0.0001), 3.60 log10 for AHP (P < 0.0001), 1.66 log10 for HAL (P < 0.0001) and 0.32 log10 for FOG (P = 0.004). QAC, AHP and HAL reduced MRSP cfu by 99.97%, 99.98% and 97.81%, respectively. FOG reduced cfu by 52.14%. CONCLUSIONS AND CLINICAL IMPORTANCE: QAC and AHP effectively disinfected surfaces inoculated with MRSP. Although HAL provided lower MRSP reduction, it may be considered clinically acceptable. FOG as a sole means of MRSP disinfection was not supported yet may have utility as an adjunctive disinfectant in clinical areas with bacterial densities lower than our experimental inoculum.

Polysulfated Glycosaminoglycan as a Novel, Adjunctive Therapy for Pemphigus Foliaceus in Three Dogs.

Three dogs who were presented with cutaneous lesions and had histopathologic findings consistent with pemphigus foliaceus were treated with injectable polysulfated glycosaminoglycan as an adjunctive to systemic immune-modulatory therapy. These patients were not adequately controlled with oral glucocorticoids in conjunction with cyclosporine, azathioprine, and/or mycophenolate. Polysulfated glycosaminoglycan contributed to induction of remission and reduced glucocorticoid doses in all dogs.

Antivenin-associated serum sickness in a dog.

OBJECTIVE: To describe a case of documented serum sickness in a dog following administration of a single dose of a novel antivenin crotalidae polyvalent. CASE SUMMARY: A 4-year-old female neutered mixed breed dog developed recurrent signs of hypersensitivity (swelling, edema, urticaria/hives, gastrointestinal signs, vasculitis) at 1 and 2 weeks following administration of a single unit of a novel antivenin crotalidae polyvalent plasma product. Both episodes were treated with antihistamines and glucocorticoids and signs improved rapidly, with a prolonged course of glucocorticoids and antihistamines administered following the second occurrence. Diagnosis of serum sickness was based on clinical appearance of delayed hypersensitivity following exposure to novel biologic product, absence of other inciting cause of hypersensitivity, complement testing, and skin biopsies confirming vasculitis. NEW OR UNIQUE INFORMATION PROVIDED: This case documents the first report of delayed hypersensitivity with a novel antivenin plasma product. This is the only case report of serum sickness to a single unit of antivenin. Additionally, the dog developed recurrence of hypersensitivity following the initial episode at 1 week; appropriate identification and prolonged treatment could have prevented recurrence and additional hospitalization. Cost and benefit analysis should be considered with antivenin administration.

Sterile Pyogranulomatous Dermatitis and Panniculitis.

Canine sterile pyogranulomatous dermatitis and panniculitis is an infrequently described syndrome. No autoantigen, or exogenous antigen, inflammatory stimulus has been identified. This syndrome is characterized by pyogranulomatous nodules, plaques, and ulcers of variable extent and severity. Prodromal and concurrent nonspecific clinical and hematologic signs of inflammation may occur. This waxing and waning condition is typically responsive to systemic immunomodulation. Lifelong therapy may be required to prevent relapse. Differential diagnoses include bacterial and fungal nodular dermatoses, neoplasia, and cutaneous reactive histiocytosis. Diagnosis is achieved via diagnostic exclusion of infectious causes and supportive histopathology findings.

A retrospective analysis of the use of lokivetmab in the management of allergic pruritus in a referral population of 135 dogs in the western USA.

BACKGROUND: Lokivetmab neutralizes IL-31, a cytokine that plays an important role in the pathogenesis of atopic dermatitis (AD) in dogs. OBJECTIVE: To review experience of one year of treatment with lokivetmab for the control of pruritus in dogs with allergic dermatitis. ANIMALS: Eighty dogs diagnosed with AD, ten with concurrent adverse food reaction and AD and 45 with allergic dermatitis of undetermined cause. Three dogs were lost to follow- up. METHODS AND MATERIALS: Retrospective analysis of medical records of dogs with allergic dermatitis treated with lokivetmab from November 2015 to October 2016. Treatment success for owner-assessed pruritus was empirically defined as ≥2 cm reduction in Visual Analog Scale (pVAS) from baseline. A ≥50% reduction in pVAS also was recorded. RESULTS: Pruritus improvement was achieved in 116 of 132 dogs (87.8%) following initial lokivetmab administration at 1.8 to 3.7 mg/kg (P < 0.001). A pVAS reduction of ≥50% was recorded in 104 dogs (77.0%). Dogs with severe/very severe pruritus prior to treatment and large/giant sized dogs, had 2.7 and 2.8 times higher odds of treatment success, respectively. There were no significant associations between treatment success and age of onset of clinical signs, disease chronicity, lokivetmab dosage or age at initial lokivetmab administration. Dogs that did not previously respond to oclacitinib were less likely to respond to lokivetmab. Adverse effects including lethargy, vomiting, hyperexcitability, pain at injection site and urinary incontinence were reported in 11 of 132 dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: Lokivetmab at labelled dosages was a fast, safe and efficacious therapy for the control of pruritus in dogs with allergic dermatitis.

Evaluation of immunological parameters in pit bull terrier-type dogs with juvenile onset generalized demodicosis and age-matched healthy pit bull terrier-type dogs.

BACKGROUND: Juvenile onset generalized demodicosis (JOGD) is thought to occur due to immunological abnormalities and is over-represented in pit bull terrier-type dogs. ANIMALS: Twelve pit bull terrier-type dogs with JOGD and 12 age-matched healthy pit bull terrier-type dogs. OBJECTIVE: To investigate immunological differences between age-matched healthy and JOGD pit bull terrier-type dogs by flow cytometry, multiplex, molecular and serological assays. METHODS AND MATERIALS: Flow cytometry quantified B cells expressing MHCII or surface-bound IgG, CD4+ T cells expressing MHCII, CD8 T cells expressing MHCII or CD11a, neutrophil and monocyte markers. Surface expression was quantified by calculating the geometric mean fluorescence index. The Wilcoxon rank sum test was used to compare median results for IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, IL-13, IL-18, FOXP3, monocyte chemoattractant protein-1, GM-CSF, KC, IgE, IgA, IgG, IgM, C-reactive protein, lymphocyte, neutrophil and monocyte in the groups. IFN-gamma, IP-10, IL-15, IL-31 and TNF-alpha also were measured; however, insufficient dogs (<5) had values that were in range of the assay to allow for statistical evaluation. Significance was defined as P < 0.05. RESULTS: Serum concentrations of IL-2, IL-18 and MCP-1 were significantly higher (P = 0.01, P = 0.01, P = 0.04) in the JOGD group. Also, IgA median value was significantly higher (P = 0.002) in pit bull terrier-type dogs with JOGD. Flow cytometry revealed that T-cell, neutrophil and monocyte markers were not different between groups. CONCLUSIONS: Results suggest an appropriate compensatory immune response by pit bull terrier-type dogs in the JOGD group and do not support the explanation of global immune deficiency in these dogs.

The frequency of urinary tract infection and subclinical bacteriuria in dogs with allergic dermatitis treated with oclacitinib: a prospective study.

BACKGROUND: Oclacitinib is a selective Janus kinase inhibitor for the treatment of canine allergic pruritus and atopic dermatitis in dogs. Glucocorticoids and ciclosporin increase urinary tract infection (UTI) frequency in dogs with inflammatory skin disease. OBJECTIVE: Prospective study to evaluate the frequency of UTI and subclinical bacteriuria in dogs with allergic dermatitis receiving oclacitinib. METHODS: Client-owned dogs ≥2 years of age with a history of allergic dermatitis without apparent history of urinary tract disease or predisposition to UTI were included. Prior to enrolment, urinalysis and quantitative urine culture were performed after a washout period of at least 14 days from systemic antimicrobial drugs and 28 days for ciclosporin and systemic glucocorticoids. Dogs received oclacitinib at labelled dosing for an intended period of 180-230 days with a follow-up urinalysis and urine culture performed regardless of urinary tract signs. Systemic antimicrobial and immune-modulating drugs were not administered during the study. RESULTS: None of the 55 dogs in this study developed UTI while receiving oclacitinib based on follow-up urinalysis and urine culture performed during a range of 58-280 days (mean 195 days). Two dogs developed self-limiting abnormal urinary tract signs without urine culture or urinalysis findings consistent with UTI. CONCLUSIONS AND CLINICAL IMPORTANCE: These findings indicate that bacteriuria is not an expected adverse effect in dogs treated with oclacitinib without a prior history of UTI or predisposing condition during this treatment period. Therefore, routine urine culture is not indicated for such dogs in the absence of abnormal urinalysis or clinical signs of urinary tract disease.

Cutaneous and systemic blastomycosis, hypercalcemia, and excess synthesis of calcitriol in a domestic shorthair cat.

A 9 yr old domestic shorthair cat was diagnosed with cutaneous and pulmonic blastomycosis. Severe persistent ionized hypercalcemia and excess circulating concentration of calcitriol were documented in association with blastomycosis. Ionized hypercalcemia resolved when the granulomatous lesions of blastomycosis resolved and the calcitriol levels decreased.

Evaluation of Clinical Laboratory Standards Institute interpretive criteria for methicillin-resistant Staphylococcus pseudintermedius isolated from dogs.

The Clinical and Laboratory Standards Institute published in 2008 new interpretive criteria for the identification of methicillin resistance in staphylococci isolated from animals. The sensitivity of the 2008 interpretive criteria for mecA gene-positive Staphylococcus pseudintermedius, compared with the previous criteria of 2004, was investigated. Thirty clinical isolates of methicillin-resistant S. pseudintermedius from dogs were used. The presence of the mecA gene was determined by polymerase chain reaction. The minimum inhibitory concentration for oxacillin was determined by broth microdilution. The 2008 breakpoint of >or=4 microg/ml for methicillin resistance resulted in a diagnostic sensitivity of 73.3% (22/30). The 2004 breakpoint guideline of >or=0.5 microg/ml resulted in a diagnostic sensitivity of 97% (29/30). For oxacillin disk diffusion, the 2008 interpretive criterion of

Feline lentiviruses demonstrate differences in receptor repertoire and envelope structural elements.

Feline immunodeficiency virus (FIV) causes fatal disease in domestic cats via T cell depletion-mediated immunodeficiency. Pumas and lions are hosts for apparently apathogenic lentiviruses (PLV, LLV) distinct from FIV. We compared receptor use among these viruses by: (1) evaluating target cell susceptibility; (2) measuring viral replication following exposure to specific and non-specific receptor antagonists; and (3) comparing Env sequence and structural motifs. Most isolates of LLV and PLV productively infected domestic feline T cells, but differed from domestic cat FIV by infecting cells independent of CXCR4, demonstrating equivalent or enhanced replication following heparin exposure, and demonstrating substantial divergence in amino acid sequence and secondary structure in Env receptor binding domains. PLV infection was, however, inhibited by CD134/OX40 antibody. Thus, although PLV and LLV infection interfere with FIV superinfection, we conclude that LLV and PLV utilize novel, more promiscuous mechanisms for cell entry than FIV, underlying divergent tropism and biological properties of these viruses.