Update on the role of genetic factors, environmental factors and allergens in canine atopic dermatitis.

BACKGROUND: Canine atopic dermatitis (cAD) is a common, complex and multifactorial disease involving, among others, genetic predisposition, environmental factors and allergic sensitisation. OBJECTIVE: This review summarises the current evidence on the role of genetic and environmental factors and allergic sensitisation in the pathogenesis of cAD since the last review by ICADA in 2015. MATERIALS AND METHODS: Online citation databases and proceedings from international meetings on genetic factors, environmental factors and allergens relevant to cAD that had been published between 2015 and 2022 were reviewed. RESULTS: Despite intensive research efforts, the detailed genetic background predisposing to cAD and the effect of a wide range of environmental factors still need more clarification. Genome-wide association studies and investigations on genetic biomarkers, such as microRNAs, have provided some new information. Environmental factors appear to play a major role. Lifestyle, especially during puppyhood, appears to have an important impact on the developing immune system. Factors such as growing up in a rural environment, large size of family, contact with other animals, and a nonprocessed meat-based diet may reduce the risk for subsequent development of cAD. It appears that Toxocara canis infection may have a protective effect against Dermatophagoides farinae-induced cAD. House dust mites (D. farinae and D. pteronyssinus) remain the most common allergen group to which atopic dogs react. Currently, the major allergens related to D. farinae in dogs include Der f 2, Der f 15, Der f 18 and Zen 1. CONCLUSIONS AND CLINICAL RELEVANCE: Canine atopic dermatitis remains a complex, genetically heterogeneous disease that is influenced by multiple environmental factors. Further, well-designed studies are necessary to shed more light on the role of genetics, environmental factors and major allergens in the pathogenesis of cAD.

Update on the skin barrier, cutaneous microbiome and host defence peptides in canine atopic dermatitis.

BACKGROUND: Canine atopic dermatitis (AD) is a complex inflammatory skin disease associated with cutaneous microbiome, immunological and skin barrier alterations. This review summarises the current evidence on skin barrier defects and on cutaneous microbiome dysfunction in canine AD. OBJECTIVE: To this aim, online citation databases, abstracts and proceedings from international meetings on skin barrier and cutaneous microbiome published between 2015 and 2023 were reviewed. RESULTS: Since the last update on the pathogenesis of canine AD, published by the International Committee on Allergic Diseases of Animals in 2015, 49 articles have been published on skin barrier function, cutaneous/aural innate immunity and the cutaneous/aural microbiome in atopic dogs. Skin barrier dysfunction and cutaneous microbial dysbiosis are essential players in the pathogenesis of canine AD. It is still unclear if such alterations are primary or secondary to cutaneous inflammation, although some evidence supports their primary involvement in the pathogenesis of canine AD. CONCLUSION AND CLINICAL RELEVANCE: Although many studies have been published since 2015, the understanding of the cutaneous host-microbe interaction is still unclear, as is the role that cutaneous dysbiosis plays in the development and/or worsening of canine AD. More studies are needed aiming to design new therapeutic approaches to restore the skin barrier, to increase and optimise the cutaneous natural defences, and to rebalance the cutaneous microbiome.

Update on the role of cytokines and chemokines in canine atopic dermatitis.

BACKGROUND: Cytokines and chemokines play central roles in the pathogenesis of canine atopic dermatitis (cAD). Numerous studies have been published and provide new insights into their roles in cAD. OBJECTIVES: To summarise the research updates on the role of cytokines and chemokines in the pathogenesis of cAD since the last review by the International Committee on Allergic Diseases of Animals in 2015. MATERIAL AND METHODS: Online citation databases, abstracts and proceedings from international meetings on cytokines and chemokines relevant to cAD that had been published between 2015 and 2022 were reviewed. RESULTS: Advances in technologies have allowed the simultaneous analysis of a broader range of cytokines and chemokines, which revealed an upregulation of a multipolar immunological axis (Th1, Th2, Th17 and Th22) in cAD. Most studies focused on specific cytokines, which were proposed as potential novel biomarkers and/or therapeutic targets for cAD, such as interleukin-31. Most other cytokines and chemokines had inconsistent results, perhaps as a consequence of their varied involvement in the pathogenesis of different endotypes of cAD. CONCLUSIONS AND CLINICAL RELEVANCE: Inconsistent results for many cytokines and chemokines illustrate the difficulty of studying the complex cytokine and chemokine networks in cAD, and highlight the need for more comprehensive and structured studies in the future.

Cytokine transcriptome profiling in acute experimental canine atopic dermatitis skin lesions after IL-31 inhibition with lokivetmab.

BACKGROUND: The caninised monoclonal antibody lokivetmab (LKV), directed at interleukin (IL)-31, is very effective at controlling pruritus in most dogs with atopic dermatitis (AD). However, evidence exists that IL-31 is not required for the induction of acute allergic skin inflammation, which might explain why this treatment is less efficacious in some dogs with AD. HYPOTHESIS/OBJECTIVES: To compare the comprehensive transcriptome analysis of house dust mite (HDM)-sensitised dogs with and without treatment with LKV to attest our hypothesis that LKV does not majorly affect acute cytokine/chemokine production. ANIMALS: Six HDM-sensitised atopic Maltese-beagle dogs. MATERIALS AND METHODS: In this cross-over study, the cytokine profiling of acute AD skin lesions was compared by RNA sequencing (RNA-Seq), with or without LKV-induced inhibition of IL-31. Skin biopsies were obtained from each dog at 0, 6, 12, 24, 48, and 96 h after epicutaneous HDM allergen provocation. RESULTS: Macroscopic and microscopic skin lesion scores were not significantly different between the LKV- and nontreatment groups at any time points. Likewise, the results of RNA-Seq analysis revealed no significant difference in the messenger (m)RNA expression of the major cytokines between these two groups. In LKV-treated dogs, IL6, IL9, IL13, IL33, CCL17, and CCL22 were significantly upregulated compared to their baseline expression levels, suggesting that these cytokines are unaffected by IL-31 inhibition. CONCLUSIONS AND CLINICAL RELEVANCE: IL-31 inhibition is insufficient to prevent the expression of other proinflammatory mediators in acute AD and these could be considered as other potential therapeutic targets.

IL-31 and IL-31 receptor expression in acute experimental canine atopic dermatitis skin lesions.

BACKGROUND: To optimise the interleukin (IL)-31-blocking therapy in atopic dermatitis (AD), an understanding of the chronology in the expression of IL-31 and its receptor (IL-31RA) is needed. HYPOTHESIS/OBJECTIVES: (i) To assess the chronological expression of IL-31 in canine AD skin lesions, (ii) to compare it with serum IL-31 levels and macroscopic skin lesion scores, and (iii) to determine the identity of IL-31- and IL-31RA-positive cells. ANIMALS: Four atopic dogs sensitised to house dust mites. METHODS AND MATERIALS: Skin and blood samples were obtained 0 h, 24 h, 48 and 96 h after allergen provocation. IL-31 and IL-31RA single-staining immunofluorescence (IF), as well as IL-31/CD3, IL-31/CD4 and IL-31RA/ß3-tubulin double-staining IF were performed. The IL-31-positive cells were counted subjectively. RESULTS: The peak IL-31 expression for three of four dogs occurred 24 h or 48 h postchallenge; it started to decrease at 96 h. There was no significant correlation between the IL-31 expression scores and the serum IL-31 concentrations or the macroscopic skin lesion scores (P = 0.35 and P = 0.36, respectively). The majority of IL-31-positive cells were positive for CD3 (range 91-100%) and CD4 (range 63-100%), indicating that they were helper T (Th) cells. Unexpectedly, sebaceous glands were strongly immunolabelled with IL-31; the extinction of this positivity after immunoabsorption with IL-31 further supported the validity of this immunostaining. The IL-31RA was visualised on keratinocytes and a small proportion of dermal nerves. CONCLUSIONS AND CLINICAL IMPORTANCE: The early and transient production of IL-31 by Th cells supports the concept of using IL-31 inhibiting strategies as a proactive therapy to prevent flares of AD skin lesions.

Efficacy study of a topical treatment with a plant extract with antibiofilm activities using an in vivo model of canine superficial pyoderma.

BACKGROUND: Canine pyoderma is a common skin infection caused predominantly by staphylococcal bacteria. Because of increasing rates of antimicrobial resistance in bacterial isolates, there is an urgent need for alternative or supplementary treatment options. W16P576, a Water Extract of Complex Mix of Edible Plants (WECMEP), has shown in vitro activity against a variety of bacteria, including Staphylococcus pseudintermedius. A canine model of pyoderma was developed which allows in vivo testing of antimicrobial agents in a controlled environment. OBJECTIVE: To evaluate the antibacterial efficacy of topical application of W16P576 in a model of canine pyoderma. ANIMALS: Nine laboratory housed beagle dogs. METHODS AND MATERIALS: In an evaluator-blinded cross-over study with an eight week washout period, dogs were treated topically twice daily with W16P576 WECMEP or its vehicle, starting three days before bacterial challenge. On the day of challenge, each dog was treated with two concentrations of a clinical S. pseudintermedius strain on opposite sides of the body. Topical treatment was continued for 11 days and lesions of pyoderma were evaluated and scored for 14 days. RESULTS: All dogs developed lesions consistent with bacterial pyoderma. Lesion scores were generally higher on the side inoculated with a higher concentration of bacteria. Treatment with W16P576 significantly reduced lesion development and hastened resolution of lesions, compared to placebo. CONCLUSION: Topical application of W16P576 markedly reduced lesion development in this proof of principle study. Clinical trials are warranted to estimate benefits for dogs with naturally occurring pyoderma under field conditions.

Proactive maintenance therapy of canine atopic dermatitis with the anti-IL-31 lokivetmab. Can a monoclonal antibody blocking a single cytokine prevent allergy flares?

BACKGROUND: Once the signs of canine atopic dermatitis (AD) are controlled, the proactive application of topical glucocorticoids can delay disease flares. OBJECTIVES: We wished to determine if the proactive administration of the anti-IL-31 lokivetmab would prevent or delay flares of canine AD. ANIMALS: We tested this strategy in four Maltese-beagle atopic dogs before enrolling 21 dogs with spontaneous AD. METHODS AND MATERIALS: In our acute AD model, house dust mite (HDM)-sensitized dogs were injected once with lokivetmab. After seven days, an HDM suspension was applied epicutaneously, and both skin lesions and pruritus manifestations were quantified for 24 h. In a second study, 21 dogs with spontaneous AD controlled with anti-allergic drugs were treated with lokivetmab per manufacturer's recommendations; all anti-allergic drugs were discontinued within four weeks after the first injection. All dogs were followed prospectively for at least one year and the time-to-flare (TTF) of AD after the last day of anti-allergic treatment was determined. RESULTS: In the experimental study, one injection of lokivetmab prevented nearly all expected allergen-induced pruritus manifestations but not skin lesion development. In dogs with spontaneous AD, the median TTF after lokivetmab proactive therapy was 63 days. One-fourth of dogs did not exhibit a flare for at least one year while receiving lokivetmab monotherapy. CONCLUSIONS: Although lokivetmab seems more effective to prevent pruritus than skin lesions in dogs with experimental AD' it also can delay disease flares in some dogs with the spontaneous disease. Studies are needed to identify those patients most likely to respond to such a proactive regimen.

Pilot evaluation of the antipruritic efficacy of a topical transient receptor potential melastatin subfamily 8 (TRPM8) agonist in dogs with atopic dermatitis and pedal pruritus.

BACKGROUND: Atopic dermatitis (AD) requires a multimodal therapy and there is a need for effective adjunctive interventions. TRPM8 agonists are known to alleviate pruritus by inducing cooling. OBJECTIVES: To evaluate the efficacy of a novel TRPM8 agonist, 1-diisopropylphosphorylheptane (Cryosim-1), in atopic dogs. ANIMALS: Nine client owned dogs with moderate to severe pedal pruritus associated with nonseasonal AD. METHODS: This was a prospective, randomized, double-blinded, intraindividual, placebo-controlled study. A 2% Cryosim-1 or placebo-vehicle cream was applied to each forepaw twice daily for seven days. The owner rated the pruritus manifestations once daily using a pedal Pruritus Visual Analog Scale (PVAS) and provided a Owner's Global Assessment of Treatment Efficacy (OGATE) at study end. RESULTS: After seven days, the numbers of dogs with a pedal PVAS <2.0 for Cryosim-1 and placebo were three and five of nine, respectively; likewise, OGATE scores of good-to-excellent were two and five of eight, respectively - these proportions were not significant between treatment groups (P = 0.32 and 0.16, respectively). Furthermore, there was no significant difference between Cryosim-1 and placebo in the median percentage change from baseline PVAS (47% versus 75%; P = 0.15) and in the number of dogs with a ≥50% or a ≥90% reduction from baseline pedal PVAS (four of nine versus five of nine, P = 0.50; two of nine versus two of nine, P = 0.72). CONCLUSIONS: In this pilot trial with a TRPM8 agonist in atopic dogs with pedal pruritus, the twice daily application of a 2% Cryosim-1 cream did not have an antipruritic effect superior to that of its vehicle.

Autosomal recessive congenital ichthyosis due to PNPLA1 mutation in a golden retriever-poodle cross-bred dog and the effect of topical therapy.

BACKGROUND: Ichthyoses represent a genetically and phenotypically heterogeneous syndrome of abnormal epidermal cornification. Although the clinical presentation, histopathological findings and genetic cause of autosomal recessive congenital ichthyosis (ARCI) in golden retriever dogs have been well investigated, the optimal management of this disease remains uncharacterized. OBJECTIVES: In this report we describe the beneficial effect of oral and topical fatty acids for management of a golden retriever and poodle cross-bred dog (goldendoodle) with ARCI due to a PNPLA1 (Patatin-like phospholipase domain containing 1) mutation. CASE REPORT: A six-month-old, intact female, second generation golden retriever and poodle cross-bred dog presented with a history of generalized scaling since the age of 6 weeks. Histopathology showed diffuse, laminated-to-compact hyperkeratosis with a single small perinuclear vacuole in occasional stratum granulosum keratinocytes. Genetic testing revealed a homozygotic insertion/deletion mutation in the gene PNPLA1. Daily oral fatty acid supplementation and humectant rinse, following weekly moisturizing shampoo, resulted in only mild improvement after two months. Weekly application of a topical essential oils and fatty acid product was then added. Thirteen months after the initial presentation the dog exhibited a marked improvement in clinical signs. The temporal discontinuation of topical therapy resulted in the worsening of scaling, which improved again after resuming this combination. CONCLUSIONS AND CLINICAL IMPORTANCE: To the best of the authors' knowledge, this is the first case report of ARCI with homozygous PNPLA1 mutation in a golden retriever-poodle cross-bred dog. The long-term combination of oral fatty acids and topical therapy appeared to be beneficial in this case.