Tim Nuttall

Treatment of canine atopic dermatitis: 2010 clinical practice guidelines from the International Task Force on Canine Atopic Dermatitis

Atopic dermatitis (AD) is a common chronic relapsing pruritic skin disease of dogs for which treatment has varied over time and geographical location. Recent high quality randomized controlled trials and systematic reviews have established which drugs are likely to offer consistent benefit. The International Task Force for Canine AD currently recommends a multi-faceted approach to treat dogs with AD. Acute flares should be treated with a combination of nonirritating baths and topical glucocorticoids, once an attempt has been made to identify and remove the suspected causes of the flare. Oral glucocorticoids and antimicrobial therapy must be added when needed. In dogs with chronic AD, a combination of interventions should be considered. Again, factors that trigger flares of AD must be identified and, if possible, avoided. Currently recognized flare factors include food, flea and environmental allergens, Staphylococcus bacteria and Malassezia yeast. Skin and coat hygiene and care must be improved by bathing with nonirritating shampoos and dietary supplementation with essential fatty acids. The severity of pruritus and skin lesions can be reduced with a combination of anti-inflammatory drugs. Currently, medications with good evidence of high efficacy include topical and oral glucocorticoids, and calcineurin inhibitors such as oral ciclosporin and topical tacrolimus. The dose and frequency of administration of these drugs should be tailored to each patient considering each drugs efficacy, adverse effects and cost. Allergen-specific immunotherapy should be offered, whenever feasible, in an attempt to prevent recurrence of clinical signs upon further exposure to environmental allergens to which the patient is hypersensitive.

Expression of Th1, Th2 and immunosuppressive cytokine gene transcripts in canine atopic dermatitis

Background Atopic dermatitis is a common inflammatory skin disease of humans and dogs. Human atopic dermatitis is associated with Th2‐type responses, although Th1 cytokines can be identified in chronic lesions. In contrast, tolerance to environmental allergens in healthy individuals is mediated by regulatory T cells.

Staphylococcal colonization of mucosal and lesional skin sites in atopic and healthy dogs.

Staphylococcal colonization was compared in healthy dogs and in dogs with atopic dermatitis. Bacterial swabs were collected from the nasal mucosa, ear and perineum of 43 healthy and 24 atopic dogs and also from potentially infected skin lesions of the atopic dogs. Coagulase positive staphylococcal isolates were identified to the species level. At the time of this study Staphylococcus intermedius was considered a single species but has since been recognized as comprising at least three species with canine isolates believed to belong to Staphylococcus pseudintermedius. Of atopic dogs, 87.5% were colonized with S. intermedius compared to only 37.2% of healthy dogs. The ear was the only carriage site that showed any significant difference in S. intermedius isolation between healthy and atopic dogs. The perineum represented the most frequently colonized mucosal site for both groups. Sampling the nasal mucosa alone identified 71.4% of atopic and 37.5% of healthy S. intermedius carriers. Inclusion of a perineal swab identified 100% of atopic and 93.8% of healthy carriers. S. intermedius was isolated from all the lesional sites sampled from atopic dogs. Significantly fewer dogs were colonized by Staphylococcus aureus than S. intermedius, and there was no significant difference between S. aureus colonization of atopic and healthy dogs. S. aureus was not recovered from any lesions in atopic dogs. The results show that S. intermedius carriage is more prevalent in atopic dogs compared to healthy dogs and that to identify staphylococcal carriers both the nasal mucosa and the perineum should be sampled.

T-helper 1, T-helper 2 and immunosuppressive cytokines in canine atopic dermatitis.

Atopic dermatitis is a common inflammatory skin disease of humans and dogs. Human atopic dermatitis is associated with T-helper (Th) 2 type responses, although Th1 cytokines are present in chronic lesions. This study used semi-quantitative reverse transcriptase polymerase chain reactions to determine the expression of gene transcripts for immunosuppressive cytokines (transforming growth factor beta [TGFbeta] and interleukin [IL]-10), Th2 type cytokines (IL-4 and IL-6) and Th1 type cytokines (interferon gamma [IFNgamma], tumour necrosis factor alpha [TNFalpha], IL-2 and IL-12) in lesional atopic, non-lesional atopic and healthy canine skin. Canine atopic dermatitis was associated with over-expression of IL-4 mRNA and reduced transcription of TGFbeta compared to healthy skin (ANOVA, p<0.05). Higher levels of IFNgamma, TNFalpha and IL-2 mRNA were seen in lesional compared to non-lesional and healthy skin (p<0.05). There were no significant differences in IL-10, IL-6 or IL-12 transcription. This is the first report to demonstrate that canine atopic dermatitis is associated with over-production of IL-4 and under expression of TGFbeta.

Gene expression in canine atopic dermatitis and correlation with clinical severity scores

BACKGROUND Canine atopic dermatitis (cAD) is a common condition in dogs that may be a naturally occurring model for human atopic dermatitis (hAD). Despite this, comparative research is limited, particularly into the genetic background of cAD. OBJECTIVES 1. Measure candidate gene expression in cAD skin using quantitative real time PCR (qPCR). 2. Correlate gene expression to clinical cAD scores (Canine Atopic Dermatitis Extent and Severity Index[CADESI]-03 and intradermal allergen test [IDT]). METHODS mRNA was extracted from biopsies of non-lesional and lesional skin from atopic dogs, and healthy skin from non-atopic dogs. Gene expression was quantified using qPCR, and compared between non-lesional atopic, lesional atopic and healthy skin. Gene expression in atopic skin was correlated with clinical severity (CADESI-03) and the number of positive reactions on an IDT. RESULTS Of the 20 quantified genes, 11 demonstrated statistically significant altered mRNA expression between atopic and healthy skin; dipeptidyl-peptidase-4 (DPP4), phosphatidylinositol-3,4,5-trisphosphate-5-phosphatase-2 (INPPL1), serine protease inhibitor kazal type-5 (SPINK5), sphingosine-1-phosphate lyase-1 (SGPL1), peroxisome proliferator-activated receptor gamma (PPARgamma), S100 calcium-binding protein A8 (S100A8), Plakophilin-2 (PKP2), Periostin (POSTN), Cullin4A, TNF-alpha and metalloproteinase inhibitor-1 (TIMP-1). Three genes correlated with CADESI-03: serum amyloid A 1 (SAA-1), S100A8, and PKP2; and four with IDT results: mast cell protease I (CMA1), SAA-1, S100A8 and SPINK5. CONCLUSION Genes with altered expression included those relevant to skin barrier formation and immune function, suggesting both are relevant in the pathogenesis of AD. Many of these genes reflect the proposed pathogenesis in hAD, supporting the use of dogs as a model for hAD. Furthermore, these genes may be considered suitable targets for future genetic and protein function studies in human and canine AD.

Treatment of canine atopic dermatitis: 2015 updated guidelines from the International Committee on Allergic Diseases of Animals (ICADA)

BackgroundIn 2010, the International Task Force on Canine Atopic Dermatitis (now International Committee on Allergic Diseases of Animals, ICADA) published the first consensus guidelines for the treatment of atopic dermatitis (AD) in dogs. This is the first 5-year minor update of this document.ResultsThe treatment of acute flares of AD should involve the search for, and then elimination of, the cause of the flares, bathing with mild shampoos, and controlling pruritus and skin lesions with interventions that include topical and/or oral glucocorticoids or oclacitinib. For chronic canine AD, the first steps in management are the identification and avoidance of flare factors, as well as ensuring that there is adequate skin and coat hygiene and care; this might include more frequent bathing and possibly increasing essential fatty acid intake. The medications currently most effective in reducing chronic pruritus and skin lesions are topical and oral glucocorticoids, oral ciclosporin, oral oclacitinib, and, where available, injectable recombinant interferons. Allergen-specific immunotherapy and proactive intermittent topical glucocorticoid applications are the only interventions likely to prevent or delay the recurrence of flares of AD.ConclusionsThis first 5-year minor update of the international consensus guidelines for treatment of AD in dogs further establishes that the treatment of this disease is multifaceted, and that interventions should be combined for a proven (or likely) optimal benefit. Importantly, treatment plans are likely to vary between dogs and, for the same dog, between times when the disease is at different stages.

Suggested guidelines for using systemic antimicrobials in bacterial skin infections: part 2— antimicrobial choice, treatment regimens and compliance

Systemic antimicrobials are critically important in veterinary healthcare, and resistance is a major concern. Antimicrobial stewardship will be important in maintaining clinical efficacy by reducing the development and spread of antimicrobial resistance. Bacterial skin infections are one of the most common reasons for using systemic antimicrobials in dogs and cats. Appropriate management of these infections is, therefore, crucial in any policy for responsible antimicrobial use. The goals of therapy are to confirm that an infection is present, identify the causative bacteria, select the most appropriate antimicrobial, ensure that the infection is treated correctly, and to identify and manage any underlying conditions. This is the second of two articles that provide evidence-led guidelines to help practitioners address these issues. Part 1 discussed the use of clinical signs, cytology and culture in diagnosis. This article will cover the rationale for topical and systemic antimicrobial therapy, including choice of first-, second- and third-line drugs, the dose, duration of therapy, compliance and identification of underlying predisposing conditions. In addition, there is guidance on cases of therapeutic failure and environmental hygiene. These guidelines will help veterinarians avoid the development and propagation of antimicrobial-resistant bacterial strains.

Evaluation of Th1, Th2 and immunosuppressive cytokine mRNA expression within the colonic mucosa of dogs with idiopathic lymphocytic-plasmacytic colitis

The objective of this study was to evaluate the expression of the immunoregulatory and pro-inflammatory cytokines interleukin (IL)-2, IL-4, IL-6, IL-12p35, IL-12p40, interferon-gamma (IFN-gamma), and tumour necrosis factor-alpha (TNF-alpha), and the expression of the predominantly immunosuppressive cytokines transforming growth factor-beta (TGF-beta) and IL-10 in canine idiopathic lymphocytic-plasmacytic colitis (LPC). Semi-quantitative reverse transcriptase-polymerase chain reactions were performed using specific primers on RNA isolated from the colonic mucosa of healthy dogs, dogs with clinical signs of large intestinal disease but normal histopathology of the colon, and dogs with LPC. Canine LPC was associated with over-expression of IL-2 compared to healthy colonic mucosa (p<0.01) and the mucosa of dogs with large intestinal diarrhoea but normal histopathology (p<0.05). Higher levels of TNF-alpha mRNA were also seen in LPC compared to healthy mucosa (p<0.05). These results indicate that LPC is associated with activation of CD4+ T-helper lymphocytes and increased production of T-helper-1-type cytokines.

Despite identifying some shared gene associations with human atopic dermatitis the use of multiple dog breeds from various locations limits detection of gene associations in canine atopic dermatitis

Canine atopic dermatitis (cAD) is a common, severe pruritic and inflammatory skin disease and is a major veterinary welfare issue. This study genotyped 97 single nucleotide polymorphisms (SNPs) in 25 candidate genes in 659 dogs across eight breeds from three locations (UK, USA and Japan). These genes were selected from hAD literature, and previous cAD gene expression experiments. The aim of this study was to identify any shared gene associations between cAD and hAD. Only one SNP within the TSLP-receptor was associated with all eight breeds (corrected p=0.037). Five SNPs within Filaggrin, DPP4, MS4A2, and INPPL1 were associated with cAD, but only in certain breeds from different locations. Though these associations are broadly similar to hAD the variability of results across the breeds and locations demonstrates that a candidate gene approach using mixed breeds from different locations is not appropriate. This study therefore suggests that further candidate gene studies in cAD should be breed and location specific to increase the likelihood of finding associations with the disease.

Gene (mRNA) expression in canine atopic dermatitis: microarray analysis

Genes potentially involved in the pathology of canine atopic dermatitis (AD) were identified using gene expression microarrays. Total RNA extracted from skin biopsies was hybridized to an Agilent Technologies custom-designed 22K canine array. The arrays were analysed using Genedata Analyst software. Data were corrected for multiple hypothesis testing and tested for significance using the National Institute on Aging array analysis tool. For comparison, data were divided into separate groups: lesional atopic (n = 16), nonlesional atopic (n = 17) and healthy controls (n = 9). Fifty-four genes were differentially expressed at a significance level of 0.05 in canine AD compared to healthy controls. Sixteen genes were differentially expressed in both nonlesional and lesional atopic skin, 26 genes only in nonlesional skin and 12 only in lesional skin. These genes were associated with innate immune and inflammatory responses, cell cycle, apoptosis, barrier formation and transcriptional regulation. The most dysregulated gene in lesional skin was S100A8, which showed an almost 23-fold increase in expression. This is a pro-inflammatory cytokine located in the epidermal differentiation complex. Microarray analysis is a novel technique in canine AD. Significant changes in gene expression were identified in atopic skin. These were relevant to skin barrier formation and the immune response, suggesting that they both participate in AD. Gene expression restricted to lesional skin may be involved in inflammatory changes, whereas those shared or restricted to nonlesional skin may reflect the atopic phenotype. Investigating gene polymorphisms in the targets identified in this study will help improve our understanding of the genetic basis of this disease.