犬特应性皮炎:发病率、影响和管理策略（2024） ...

王帆

Canine Atopic Dermatitis: Prevalence, Impact, and Management Strategies

犬特应性皮炎:发病率、影响和管理策略

 

作者：Yvonne Drechsler , Charli Dong , David E Clark, Gagandeep Kaur

 

翻译：王帆

 

Abstract: Atopic dermatitis (AD) is a common inflammatory and pruritic allergic skin disease in humans and dogs worldwide. The pathogenesis of AD is multifactorial, immunologically complex, and may involve genetic factors, epidermal barrier dysfunction, microbiome changes, immune dysregulation, and allergic sensitization. Across species, prevalence of AD is on the rise. At present, there is no cure for canine AD (CAD). The treatment for CAD is multifaceted and aimed at controlling the pruritus, associated inflammation, and infections, repairing the skin barrier function, and dietary management. This review presents data on prevalence, impact, and complex immunological interactions in AD with a focus on subsequent management of the disease in the canine population. A multimodal approach for management of CAD to address varying clinical signs and responses to therapies is discussed.

Keywords: immunopathology, topical therapies, systemic therapies, pruritus, immune therapies, alarmins

摘要：特应性皮炎(AD)是世界范围内人类和犬的一种常见的炎性和瘙痒性过敏反应性皮肤病。AD的发病机制是多因素、免疫复杂的，可能涉及遗传因素、表皮屏障功能障碍、微生物组改变、免疫失调和过敏致敏等。在不同物种中，AD的发病率呈上升趋势。目前，犬AD (CAD)尚无治愈方法。CAD的治疗是多模式的，主要包括控制瘙痒、相关炎症和感染、修复皮肤屏障功能以及饮食管理。本综述介绍了AD的发病率、影响和复杂的免疫相互作用的数据，重点是在CAD的后续管理。我们讨论了管理CAD的多模式方法，以处理不同的临床症状和对治疗的反应。

关键词:免疫病理学，外部治疗，系统治疗，瘙痒，免疫治疗，危险信号分子

 

Prevalence

发病率

Canine atopic dermatitis (CAD) is a multifactorial, pruritic disease, with genetic and environmental factors playing an important role in development and pathophysiology. Skin barrier dysfunction and aberrant immune response are the characteristics of CAD.The prevalence of CAD has been estimated at 3–15%. However, as per the American College of Veterinary Dermatology (ACVD) task force on atopic dermatitis (AD), these percentages are not based on reliable epidemiological data, and the ACVD task force concluded that the actual incidence and prevalence of CAD in the canine population is not well known.

犬特应性皮炎(CAD)是一种多因素的瘙痒性疾病，遗传和环境因素在其发生发展和病理生理中起着重要作用。皮肤屏障功能障碍和免疫应答异常是CAD的特征。CAD的发病率估计为3-15%。然而，根据美国兽医皮肤病学会(ACVD)特应性皮炎(AD)工作组的说法，这些百分比并不是基于可靠的流行病学数据，ACVD工作组的结论是，CAD在犬群中的实际发病率和患病率并不清楚。

 

Comparative studies of patients presented to veterinary facilities for skin diseases can be helpful to assess prevalence. In a study of dogs presented for skin problems at 52 veterinary practices in the US, prevalence of atopic or allergic dermatitis, and atopy, was 4.7% in 31,484 dogs examined. In a study from the Small Animal Clinic at University of Montreal, 18.8% of the dogs presented for dermatological disorders of which 12.7% were atopic. A recent retrospective study from a teaching hospital in Brazil reports an upward trend in diagnosis of CAD with 25.65% AD cases of all the dogs examined. Although the numbers from these studies provide insight into the cases presented, it is difficult to derive prevalence from these studies as populations at the teaching hospitals do not represent the general canine population.

对因皮肤病到兽医机构就诊的患犬进行比较研究可能有助于评估患病率。在一项针对美国52家兽医诊所的犬的皮肤问题的研究中，在31484只接受检查的犬中，特应性皮炎或过敏性皮肤病和特应性皮炎的发病率为4.7%。蒙特利尔大学小动物诊所的一项研究显示，18.8%的犬出现了皮肤病，其中12.7%是特应性皮炎。巴西一家教学医院最近的一项回顾性研究报告称，在接受检查的所有犬中，25.65%的犬患AD, CAD的诊断呈上升趋势。虽然这些研究中的数字提供了对案例的见解，但很难从这些研究中得出患病率，因为教学医院的病例并不代表一般的犬群。

 

Although many studies provide some insight on the prevalence of CAD, these data are influenced by geographical regions, survey methods, selection of populations, types of veterinary practices, and criteria used for diagnosis of CAD and other dermatoses. The prevalence and risk of developing CAD is also influenced by environmental factors. Dogs living indoors have a higher frequency of developing CAD.In a study of Golden and Labrador retrievers, environmental factors such as living in rural areas, or with other animals, and being walked in forest areas were associated with a decreased risk of CAD development, whereas, early adoption, and living in a shed in puppyhood were associated with a higher risk of CAD development. Another study in Labrador and Golden retrievers reports factors such as dogs born in rural locations, living with other dogs, and those walked on woodlands, fields, and beaches reduced the risk of developing CAD.

虽然许多研究提供了一些关于CAD患病率的见解，但这些数据受到地理区域、调查方法、人群选择、兽医工作类型以及CAD和其他皮肤病诊断标准的影响。环境因素也会影响CAD的发病率和发病风险。生活在室内的犬患CAD的几率更高。在一项对金毛和拉布拉多犬进行的研究中，环境因素(如生活在农村地区或与其他动物一起生活，以及在森林地区行走)与CAD发生风险降低相关，而过早收养和幼年时期生活在棚中与CAD发生风险较高相关。另一项针对拉布拉多和金毛猎犬的研究报告称，出生在农村、与其他犬一起生活、在林地、田野和海滩上散步的犬等因素降低了患CAD的风险。

 

In general, the onset for clinical signs of CAD is between 4 months to 3 years of age. However, the age of onset can vary between different breeds, and thus cause a change in the prevalence reported per breed, especially if a breed is represented highly in a specific geographic area. Sex-related predispositions for CAD have not been reported, but studies have shown higher numbers in either sex. In a retrospective study from Brazil, where 25.65% of dogs presented to the teaching hospital were diagnosed with CAD, 62.4% were females. However, studies have shown that male dogs, especially neutered males, are more likely to develop CAD than intact female dogs. In a study from Australia, a higher risk in males from Pug and Bichon Frisch breeds was identified. However, it should be noticed that most studies do not notice any sex predilection for development of CAD.In another study, a negative correlation between feeding a noncommercial homemade diet of the nursing dog and the development of CAD in her litter has also been reported.

一般来说，CAD的临床症状在4月龄至3岁之间开始出现。然而，不同品种的发病年龄可能不同，从而导致每个品种报告的患病率的变化，特别是如果一个品种在特定的地理区域有很高的代表性。CAD与性别相关的易感性尚未报道，但研究表明，在雄性雌性中均有较高的发病率。在巴西的一项回顾性研究中，25.65%的犬被送到教学医院诊断为CAD，其中62.4%是雌性。然而，研究表明，雄性犬，尤其是已去势的雄性犬，比未去势的雌性犬更容易患CAD。在澳大利亚的一项研究中，巴哥犬和比熊犬的风险更高。然而，应该注意的是，大多数研究没有注意到CAD的任何性别倾向。在另一项研究中，也有报道称，给哺乳犬喂食非商业性的自制饮食与其幼崽患CAD之间存在负相关。

 

The prevalence of CAD also depends on the representation of specific breeds in geographical areas where studies are conducted. Multiple studies report that Golden Retrievers, Labrador Retrievers, West Highland Terriers, German Shepherds, and French Bulldogs are at an increased risk of developing CAD. In a study from Australia, 11 dog breeds with significantly increased odds risk for CAD were identified worldwide, such as Boxer, Labrador Retriever, Pug, Bulldog, and West Highland Terrier, and classified as predisposed. In a retrospective study from Brazil, CAD was most prevalent in mixed breed dogs, followed by Shih Tzu and Poodles. Several factors influence the breed representations in CAD, including regional popularity of the breeds, genetic susceptibility, and geographical area.

CAD的发病率也取决于研究所在地理区域的特定品种的代表性。多项研究表明，金毛寻回犬、拉布拉多寻回犬、西高地白梗、德国牧羊犬和法国斗牛犬患CAD的风险增加。在澳大利亚的一项研究中，在全球范围内发现了11种患CAD风险显著增加的犬种，如拳师犬、拉布拉多寻回犬、巴哥犬、斗牛犬和西高地白梗，并被归类为易感犬。在巴西的一项回顾性研究中，CAD在杂交犬中最常见，其次是西施犬和贵宾犬。多种因素影响CAD的品种表现，包括品种的地区流行程度、遗传易感性和地理区域。

 

Despite all the studies, it should be noted that true prevalence and incidence of CAD is hard to determine due to the complex development, presentation, and management of the disease. Many CAD cases are managed by veterinarians without a specific diagnosis, such as mild presentations of CAD that are managed symptomatically or specific clinical presentations such as chronic otitis, which may not be identified as CAD by clinicians, affecting incidence reporting. Furthermore, the influence of a variety of environmental risk factors in disease development affects the prevalence reported. Considering all the factors that can affect diagnosis and presentation of CAD, there is a need for detailed epidemiological studies on the prevalence and incidence of CAD.

尽管有这些研究，但应该指出的是，由于CAD的发展、表现和管理复杂，很难确定其真正的患病率和发病率。许多CAD病例由兽医在没有特定诊断的情况下进行管理，例如对CAD的轻度表现进行症状管理，或者对慢性耳炎等临床表现(临床医师可能无法识别为CAD)进行管理，从而影响发病率报告。此外，多种环境危险因素对疾病发展的影响也影响了所报道的发病率。考虑到所有可能影响CAD诊断和表现的因素，有必要对CAD的患病率和发病率进行详细的流行病学研究。

 

Impact

影响

The prevalence numbers discussed above indicate that CAD is a significant malady of the pet population. Veterinarians rely on clinical signs and behavior of the animal when assessing the effect of a disease on the wellbeing of pets. Diseases of pets can affect quality of life of the pets as well as that of their owners. Since 2010, several questionnaires have been developed for skin diseases in small animals, and some of these also assess owner quality of life. Some questionnaires have been validated, and assessing quality of life in therapy studies is becoming more common. In the study by Linek and Favrot, almost half of the owners of dogs with CAD reported the disease affected their own quality of life, and a majority of owners felt the disease affected their pet’s quality of life. Those effects included changes or interruptions in mood, family life, leisure activities, and sleep. Some owners were also concerned with expenses and the burden of treatment. The pet’s quality of life was affected by changes in the dog’s activities of playing, walking, and sleeping.

以上讨论的患病率数字表明，CAD是一个高发病率疾病。兽医根据动物的临床症状和行为来评估疾病对宠物健康的影响。宠物的疾病会影响宠物及其主人的生活质量。自2010年以来，针对小动物皮肤病制定了若干问卷，其中一些还评估了主人的生活质量。一些问卷已被验证，在治疗研究中评估生活质量变得越来越普遍。在Linek和Favrot的研究中，几乎一半患有CAD的犬的主人报告说，这种疾病影响了他们自己的生活质量，大多数主人认为这种疾病影响了他们的宠物的生活质量。这些影响包括情绪、家庭生活、休闲活动和睡眠的改变或中断。一些宠主还担心费用和治疗负担。宠物的生活质量受到犬玩耍、散步和睡觉活动的影响。

 

There are studies that indicate pruritus and atopic dermatitis can affect canine behavior in negative ways. One study found increases in behaviors associated with fear, anxiety, aggression, and decreased trainability. Another study did not find increases in fear and anxiety behaviors, while an increase in numerous unwanted or problem behaviors was identified, along with a decrease in trainability. The authors postulated that behavioral changes could be related to stress associated with pruritus. Behavioral problems are potential reasons for euthanasia of companion animals. According to a study by Pegram et al, behavioral problems were one of the most common reasons for euthanasia of dogs in the United Kingdom. However, the study by Linek et al did not show increased thoughts of euthanasia by the owners.

有研究表明，瘙痒症和特应性皮炎会对犬的行为产生负面影响。一项研究发现，与恐惧、焦虑、攻击和可训练性降低相关的行为增加。另一项研究没有发现恐惧和焦虑行为的增加，但发现了许多不必要的或问题行为的增加，以及可训练性的降低。作者推测，行为变化可能与与瘙痒相关的压力有关。行为问题是伴侣动物安乐死的潜在原因。根据Pegram等人的研究，行为问题是英国犬安乐死的最常见原因之一。然而，Linek等人的研究并没有显示宠物主人对安乐死的想法增加。

 

CAD requires ongoing management that entails a long-term financial commitment from the pet owner, which may be a burden and could affect access to care in some instances. However, based on prevalence of the disease, the treatment and management of CAD is potentially a significant source of veterinary industry income. Information on the financial impact of CAD for patients, pet owners, and the veterinary industry, though, is limited. The inclusion of the use of quality-of-life data is helping to improve our understanding and treatment of CAD. There is a need for focused studies on the financial, pet behavioral, and human emotional impacts of CAD.

CAD需要持续的管理，需要宠物主人的长期经济承诺，这可能是一个负担，在某些情况下可能会影响护理。然而，根据该病的流行情况，对该病的治疗和管理可能是兽医行业收入的一个重要来源。然而，关于CAD对患犬、宠物主人和兽医行业的财务影响的信息是有限的。纳入生活质量数据有助于提高我们对CAD的理解和治疗。有必要对CAD对经济、宠物行为和人类情感的影响进行重点研究。

 

Immunopathology

免疫病理学

Initially, AD was understood simply as an IgE mediated allergic response or hypersensitivity I reaction, disrupting skin barrier function and activating Th2 responses. Different hypotheses were put forward, such as Outside-In with epidermal barrier dysfunction as primary cause leading to immune activation, or Inside-Out, where epidermal barrier dysfunction is secondary. However, it has become evident that there are more nuanced and complex underpinnings of the disease, involving a variety of immune cell subsets and responses, types of barrier function disruption and neuroimmune feedback loops that contribute to pathophysiology.

最初，AD被简单地理解为IgE介导的过敏反应或I型超敏反应，破坏皮肤屏障功能，激活Th2反应。提出了不同的假说，如以表皮屏障功能障碍为 原发病因导致免疫激活的由外而内假说，或以表皮屏障功能障碍为继发病因的由内而外假说。然而，目前已经明确的是，该病有更微妙和复杂的基础，涉及多种免疫细胞亚群和反应、屏障功能破坏类型和神经免疫反馈回路，这些都有助于病理生理学。

 

In healthy skin, a balance of skin barrier integrity, commensal skin microbiota, and cellular skin populations contribute to skin function and response to pathogens. Disruption of any of these factors leads to dysregulation of this balance with negative effects. Several strong candidate genes for development of AD in humans have been identified, such as mutations in filaggrin, an important epidermal protein, or immune genes found in a cluster on human chromosome 5, such as IL4, and IL13 with over 30 loci implicated. In dogs, recent genome-wide association studies (GWAS) on canine AD have also shown a strong connection with the filaggrin gene locus, and genes involved in immune responses and skin barrier function, with over 15 loci connected to CAD development.As in humans, it is not clear how many mutations in these genes contribute to CAD. Certain dog breeds, such as German Shepherd dogs and Golden and Labrador retrievers, are overrepresented in prevalence of CAD.However, while genetics play certainly a role, multiple factors including the environment and nutrition add to a complex trait such as AD, as evidenced by the fact that mutations are not found in all cases of AD, and even carriers of these mutations do not all develop AD.

在健康皮肤中，皮肤屏障完整性的平衡、共生的皮肤微生物群和皮肤细胞群有助于皮肤功能和对病原体的反应。任何这些因素的破坏都会导致这种平衡失调，并产生负面影响。目前已经确定了几个与人类AD发病相关的强候选基因，例如丝聚合蛋白(一种重要的表皮蛋白)的突变，或者在人类5号染色体上的一个簇中发现的免疫基因(如IL4和IL13)，涉及超过30个位点。在犬上，最近的全基因组关联研究(GWAS)也显示了与丝聚合蛋白基因位点，以及与免疫反应和皮肤屏障功能有关的基因有很强的联系，超过15个位点与CAD的发展有关。与人类一样，目前尚不清楚这些基因中有多少突变导致了CAD。某些品种的犬，如德国牧羊犬、金色和拉布拉多犬，在患CAD的比例过高。然而，虽然遗传确实发挥了一定的作用，但包括环境和营养在内的多种因素增加了AD这样的复杂性状，这一事实证明，突变并非在所有的AD病例中都发现，甚至这些突变的携带者也不都发展为AD。

 

Epidermal barrier disruption promotes inflammation, either due to filaggrin mutation as a primary cause, or secondary, subsequent to inflammatory/immune signaling. Other causes of skin dysbiosis occur with the itch-scratch cycle caused by irritants or allergens. These disruptions favor colonization with opportunistic microbiota, negatively affecting the skin by creating a feedback loop between immune response and epidermal inflammation. Staphylococcus spp. are commonly found in atopic lesions, in both humans (S. aureus) and dogs (S. pseudintermedius),in conjunction with overall decreased microbial diversity. Other microbiota found associated with AD skin are Malassezia, or Corynebacterium. All of these can aggravate already inflamed skin, and in several studies the use of antimicrobials and medicated shampoos has been found to be beneficial in combination with other treatments for AD, however, there is concern about increasing resistance of bacteria with the continued use of antibiotics. As with epidermal barrier dysfunction, changes in microbiota community diversity and prevalence might be primary or secondary to AD development.

表皮屏障破坏可促进炎症，其主要原因是丝聚蛋白突变，也可继发于炎症/免疫信号传导。其他引起皮肤生态失调的原因是由刺激物或过敏原引起的瘙痒-抓挠循环。这些干扰有利于机会性微生物群的定植，通过在免疫反应和表皮炎症之间创建反馈回路，对皮肤产生负面影响。葡萄球菌属常见于人(金黄色葡萄球菌)和犬(假中间型葡萄球菌)的特应性病变，与总体微生物多样性下降相关。发现与特应性皮炎皮肤相关的其他微生物群是马拉色菌，或棒状杆菌。所有这些都会加重已经发炎的皮肤，在几项研究中，抗微生物药物和含药香波的使用被发现与其他治疗特应性皮炎的方法相结合是有益的，然而，人们担心持续使用抗生素会增加细菌的耐药性。与表皮屏障功能障碍一样，微生物群落多样性和发病率的变化可能是AD发生的原发或继发因素。

 

In non-lesional skin and early acute stage of AD, tissue damage leads to the release of a class of proteins by keratinocytes, such as IL25, IL33, or thymic stromal lymphopoietin (TSLP), which are also called alarmins,and chemokines CCL17 and CCL22 (Figure 1). Alarmins are strong activators of Innate Lymphocyte Cell type 2 (ILC2) which release IL5 and IL13, both cytokines involved in TH2 signaling. ILC2 has been found in acute AD lesions of humans and mice, but have not been investigated in the skin of dogs. A study on peripheral blood in atopic dogs did not show elevated levels of these cells, which is in agreement with studies on ILCs in human patients. The alarmin TSLP has been shown to activate dermal dendritic cells to express OX40 and consequently activate naïve CD4 T cells, further amplifying a Th2 response. Expression of TSLP was significantly increased in lesional and nonlesional skin of dogs with CAD. Another aspect of alarmin release from keratinocytes, particularly TSLP and IL33, is the subsequent initiation of itch sensations. Scratching leads to more epidermal damage, followed by more release of alarmins, release of histamines from a variety of cells including mast cells, and Th2 mediated activation of IL31, which acts on sensory neurons to induce an itch sensation. The itch-scratch cycle reinforces itself and can eventually lead to thickening of the epidermis and chronic inflammation.

在非皮肤病变皮肤和AD的早期急性期，组织损伤导致角质形成细胞释放一类蛋白质，如IL25、IL33或胸腺基质淋巴细胞生成素(TSLP)，这些蛋白质也称为警报素，以及趋化因子CCL17和CCL22(图1)。警报素是固有淋巴细胞2型(ILC2)的强激活剂，ILC2释放IL5和IL13，这两种细胞因子均参与TH2信号传导。ILC2已在人类和小鼠的急性AD病变中被发现，但尚未在犬的皮肤中进行研究。对特应性皮炎犬的外周血进行的一项研究表明，这些细胞水平未升高，这与在人类患犬中进行的ILC研究一致。警报素TSLP已被证明可激活真皮树突状细胞，使其表达OX40，进而激活幼稚CD4 T细胞，进一步放大Th2应答。CAD犬皮肤病变及非皮肤病变组织中TSLP表达均明显增高。角质形成细胞释放警报素的另一个方面，特别是TSLP和IL33，是随后的瘙痒感觉的启动。搔抓导致更多的表皮损伤，随后更多的警报素释放，包括肥大细胞在内的多种细胞释放组胺，以及Th2介导的IL31激活，作用于感觉神经元诱发瘙痒感觉。瘙痒-抓挠循环会强化自身，最终导致表皮增厚和慢性炎症。

 

Chemokines CCL17 and CCL22 also induce Th2 responses, and combined, these inflammatory events lead to a selfamplifying release of IL4, IL5, IL13, and IL31, increased infiltration of CD4 and CD8 T cells, activation of B cells and IgE class switching, activation of mast cells, and recruitment of eosinophils. The key intracellular pathway involved in inflammatory and particularly Th2 signaling is Janus activated kinase/signal transducer and activator of transcription (JAK/STAT) mediated, where binding of cytokines to their cellular receptors activates JAK, leading to phosphorylation of STAT inducing gene transcription of inflammatory signaling molecules. Due to its importance in Th2 signaling, this pathway has become a major focus for drug development to combat pruritus and inflammation in AD.

趋化因子CCL17和CCL22也可诱导Th2应答，这些炎症事件结合在一起可导致IL4、IL5、IL13和IL31的自我扩增性释放，CD4和CD8 T细胞浸润增加，B细胞活化和IgE类别转换，肥大细胞活化和嗜酸性粒细胞募集。Janus活化激酶/信号转导和转录激活因子(JAK/STAT)是参与炎症尤其是Th2细胞信号传导的关键细胞内通路，细胞因子与其细胞受体结合后激活JAK，导致STAT磷酸化，从而诱导炎症信号分子的基因转录。由于其在Th2信号通路中的重要作用，该通路已成为开发抗瘙痒和炎症药物的主要焦点。

 

Aside from Th2, several studies have looked at Th1, Th9, Th17 and Th22 activation both in humans and dogs. The involvement of additional cell types and cytokines is reflective of an increasingly complex and widening adaptive immune response, transitioning to chronic disease. Th22 is associated with expression of IL22, which is present in the onset of acute lesions, progressively increasing in chronic disease. On the other hand, Th1 and Th17 tend to be more variable in chronic stages of AD, but are also associated with bacterial colonization, as both of these pathways are typically considered classic inflammatory pathogen responses. Different endotypes of atopic dermatitis in humans have been shown to reflect differences in the activation of these Th responses. As an added complication, in humans difference in Th1 vs Th22 or Th17 involvement has been associated with ethnicity, with European vs Asian subtypes, but recent transcriptomic studies reveal a rather heterogeneous pathogenesis involving Th17, Th22, and Th1 types.Dog breed-specific Th subtypes have so far not been identified.

除Th2外，还有几项研究研究了人类和犬的Th1、Th9、Th17和Th22激活。其他细胞类型和细胞因子的参与反映了越来越复杂和广泛的适应性免疫应答向慢性疾病过渡。Th22与IL22的表达相关，在急性病变开始时即存在，在慢性疾病中呈进行性增加。另一方面，Th1和Th17在AD的慢性阶段往往更多变，但也与细菌定植相关，因为这两种途径通常被认为是经典的炎症病原体反应。人类特应性皮炎的不同内型反映了这些Th反应激活的差异。另外一个并发症是，在人类中，Th1与Th22或Th17参与的差异与种族、欧洲亚型与亚洲亚型相关，但最近的转录组学研究揭示了涉及Th17、Th22和Th1类型的相当异质性的发病机制。犬种特异性Th亚型迄今尚未被确定。

 

Recent advances in single-cell transcriptomics are increasingly delineating these complex responses on a cellular level both in humans and dogs. Not only do these studies show the cellular subpopulations and detailed activated genes and pathways involved but also identify different cells previously not well investigated in the context of AD. For example, fibroblasts were identified in these single-cell sequencing studies as having a role in immunomodulation, opening up new avenues of investigation for therapeutics. In the canine study, gamma delta T cells were additionally identified as highly increased in the atopic skin of dogs, and several inflammatory markers previously not detected discovered.

单细胞转录组学的最新进展越来越多地描述了人类和犬在细胞水平上的这些复杂反应。这些研究不仅显示了细胞亚群和详细的激活基因和通路，而且还识别了以前在AD背景下没有得到很好研究的不同细胞。例如，在这些单细胞测序研究中，成纤维细胞被确定在免疫调节中发挥作用，这为治疗开辟了新的研究途径。在犬的研究中，γ δ T细胞在犬的特应性皮肤中被发现高度增加，并且发现了一些以前未检测到的炎症标志物。

 

Considering the variability of responses, but common themes such as Th2 responses, neuroinflammation and itch, the treatment of CAD has focused on the pathways involved in these areas as detailed in the following management practices.

考虑到反应的可变性，但常见的主题如Th2反应、神经炎症和瘙痒，CAD的治疗重点关注这些领域涉及的通路，如下面的管理实践中详细介绍。

 

Management of CAD

CAD管理

CAD requires a multimodal approach for management. Each dog has varying degrees of clinical signs and responses to therapies; thus, it is best to tailor the management plan for each individual patient. It is also important to emphasize that secondary infection and other factors need to be addressed for these management strategies to be effective. Clinicians should always treat for secondary bacteria and yeast pyoderma or pododermatitis prior to reaching for symptomatic care, especially when there is a sudden increase in the pruritus score or if a patient’s pruritus is localized. Of equal importance, it is pertinent to investigate other causes of pruritus with diet trials and parasite control. If there is a limited response to these management therapies, clinicians should reconsider their diagnosis. Lastly, to ensure successful long-term management, client education is most essential. Chronicity and incurable aspects of CAD in addition to expectations ought to be addressed. Frustration and ongoing expenses are common concerns, and owners should be counseled accordingly.

CAD需要多模式的管理方法。每只犬都有不同程度的临床症状和对治疗的反应;因此，最好为每个患犬量身定制治疗计划。还必须强调的是，要使这些管理策略有效，需要解决继发感染和其他因素。临床医师应在采取对症治疗之前对继发性细菌和酵母性脓皮病或足皮炎进行治疗，特别是当瘙痒评分突然增加或患犬的瘙痒局限时。同样重要的是，通过饮食试验和寄生虫控制来研究瘙痒的其他原因。如果患犬对这些治疗方案的效果有限，临床医师应重新考虑其诊断。最后，为了确保成功的长期管理，客户教育是最重要的。除了预期之外，CAD的慢性和不可治愈性方面也应该得到解决。沮丧和持续的费用是常见的问题，应向宠主提供相应的咨询。

 

Immunotherapy

免疫治疗

Allergen-specific immunotherapy (ASIT) has been at the forefront of managing AD in both humans and veterinary patients since 1911. The first report of successfully treating an allergic dog with ASIT was published in 1941. It is the most effective and proactive way to manage CAD. ASIT is generally safe, helps reduce clinical signs, and decreases the overall need for medication. ASIT refers to a mix of allergens given in progressively increasing doses and typically consists of an induction phase followed by maintenance. Traditionally, these doses are given as subcutaneous injections. Frequencies and amounts should be customized to each individual depending on the individual’s clinical responses and adverse events. The average observable clinical response occurs between six and eight months but because response rates are variable, subcutaneous ASIT should be continued for at least 1 year to properly evaluate efficacy. For some patients, especially seasonal cases, 2–3 years of follow-up are needed to make a suitable assessment. According to a retrospective study of 664 client owned dogs, more than 50% of clinical signs improved in 59.9% of atopic dogs with ASIT. Beneficial effects are notably higher if dogs are examined regularly and consistently, and if no systemic long-term corticosteroids are given in the first 9 months of therapy.Nevertheless, owner compliance is the main factor as the cause for reduced efficacy of ASIT. In another retrospective study of 145 CAD patients managed with ASIT, the duration of treatment was strongly linked with efficacy. Dogs treated for less than 1 year only showed an efficacy rate of 22% compared to dogs treated for more than 1 year (65%). In addition, concomitant medications in dogs treated for more than 1 year were reduced by 87%.

自1911年以来，过敏原特异性免疫疗法(ASIT)一直处于治疗人类和兽医AD患犬的最前沿。第一个ASIT成功治疗过敏症患犬的报告发表于1941年。它是管理CAD最有效、最主动的方法。ASIT通常是安全的，有助于减少临床症状，并减少对药物的总体需求。ASIT指的是逐渐增加剂量的混合过敏原，通常包括诱导期和维持期。传统上，这些剂量通过皮下注射给药。频率和剂量应根据个体的临床应答和不良事件定制。平均可观察到的临床缓解发生在6 ~ 8个月之间，但由于缓解率不同，皮下ASIT应持续至少1年，以正确评估疗效。对于部分患犬，尤其是季节性病例，需要2 ~ 3年的随访才能做出合适的评估。根据一项对664只家养犬的回顾性研究，在患ASIT的59.9%的特应性疾病犬中，超过50%的临床症状得到改善。如果在治疗的前9个月对犬进行定期和持续的检查，并且没有给予系统的长期皮质类固醇，则有益效果明显更高。宠主依从性是导致ASIT疗效下降的主要因素。在另一项对145例接受ASIT治疗的CAD患犬进行的回顾性研究中，治疗持续时间与疗效密切相关。治疗不到1年的犬显示出22%的有效率，而治疗超过1年的犬显示出65%的有效率。此外，在治疗超过1年的犬中，合并用药减少了87%。

 

Some clinicians, including the authors of this paper, have found RUSH (“sped-up”) immunotherapy to be an effective protocol because RUSH immunotherapy can decrease the time necessary to achieve maintenance doses as well as reducing questionable side effects monitored by owners. In RUSH protocols, doses are administered at 15–60 minute intervals over 1–3 days, until maintenance is achieved.

包括本文作者在内的一些临床医师发现，RUSH(“加速”)免疫疗法是一种有效的方案，因为RUSH免疫疗法可以减少达到维持剂量所需的时间，并减少宠主监测的可疑副作用。在RUSH方案中，在1 ~ 3日期间以15 ~ 60分钟的间隔给药，直至达到维持剂量。

 

Sublingual immunotherapy (SLIT) is a form of immunotherapy where allergens are given orally instead of by traditional subcutaneous injection. For humans, it has been an efficacious treatment and received United States regulatory approval in 2014. In people, the major use is for allergic rhinoconjunctivitis or asthma but has also been used for AD. Protocols usually include hooking the plastic dispensing nozzle over the lower arcade of teeth or the commissure, with the goal that the solution be dispensed sublingually. Protocols generally consist of an induction period ranging from lower to higher concentrations but can vary. Most protocols consist of one to two pumps twice daily. Patients should avoid eating or drinking for 10 minutes before and after administration for best absorption.

舌下免疫治疗(SLIT)是一种将过敏原口服替代传统皮下注射的免疫治疗方式。对于人类，它是一种有效的治疗方法，并于2014年获得了美国监管机构的批准。在人类中，主要用于过敏性鼻结膜炎或哮喘，但也用于AD。方案通常包括将塑料分配喷嘴钩在牙齿的下牙弓或连合上，目的是使溶液在舌下分配。方案通常包括从较低浓度到较高浓度不等的诱导期，但可能有所不同。大多数方案包括每天2次，每次1-2个泵。用药前后应避免进食或饮水10分钟，以达到最佳吸收效果。

 

Intra-lymphatic immunotherapy (ILIT) is a relatively new form of ASIT.In dogs, protocols include administration with ultrasound guidance into a lymph node, usually the popliteal, as it is the easiest lymph node to access. Induction phases can vary but one published protocol consists of one injection every 4 weeks for four treatments, followed by the maintenance phase of subcutaneous ASIT injections thereafter. In a prospective comparison study comparing three different protocols (subcutaneous ASIT, ILIT and SLIT), ILIT outperformed both groups in returning to normal and improvement. In another study, no significant differences between RUSH immunotherapy and ILIT induction protocol were noted. ILIT has been found to be safe and identical in efficacy to traditional subcutaneous ASIT.

淋巴内免疫治疗(ILIT)是一种相对较新的ASIT形式。在犬中，治疗方案包括在超声引导下进入淋巴结，通常是腘窝，因为它是最容易进入的淋巴结。诱导期可能不同，但一项已发表的方案包括每4周注射1次，共4次治疗，之后是皮下ASIT注射的维持期。在一项比较三种不同治疗方案(皮下ASIT、ILIT和SLIT)的前瞻性对照研究中，ILIT在恢复正常和改善方面优于两组。在另一项研究中，未观察到RUSH免疫疗法和ILIT诱导方案之间有显著差异。ILIT与传统皮下ASIT疗效相当，且安全性较好。

 

Currently, there is no standardization for immunotherapy protocols no matter the methodology. Protocols can be used as a starting point, but the clinician should make adjustments based on each individual patient’s response. Presently, it is essential to highlight that CAD is a diagnosis via exclusion and that neither ASIT nor IgE serologies can be used to diagnose CAD. Yet these diagnostics are helpful in identifying hypersensitivity to environmental allergies in CAD patients after a diagnosis has been made.

目前，免疫治疗方案尚无统一标准。方案可作为一个起点，但临床医师应根据每个患犬的反应做出调整。目前，有必要强调的是，CAD是一种排除诊断，ASIT和IgE血清学都不能用于诊断CAD。然而，这些诊断方法有助于在确诊后识别CAD患犬对环境过敏的超敏反应。

 

Drugs

药物

Antihistamines make a minor impact on the overall management of CAD, but they continue to be one of the most frequently used medications to manage CAD. Type I oral antihistamines include hydroxyzine, diphenhydramine, chlorpheniramine, clemastine, and dimetindene. Their principal mechanism of action was considered to interfere with histamine-mediated pruritus by blocking the histamine H1 receptor. Histamine is an inflammatory mediator released from several cells, such as mast cells and basophils, leading to further degranulation of mast cells and inflammatory cell migration and is thought to be involved in the excitation of unmyelinated C-fibers via increase in calcium in neurons, leading to itch.First-generation antihistamines block histaminic and muscarinic receptors and are able to pass the blood–brain barrier.Second-generation antihistamines predominantly block histaminic receptors and are less likely to pass blood–brain barrier. First-generation antihistamine studies tend to have conflicting results, but it can be agreed that results are generally trivial or ineffective. A randomized control trial reported that two first generation oral antihistamines, consisting of a hydroxyzine/chlorpheniramine combination (Histacalmine®, Virbac, Carros, France) and dimetindene (Fenistil®, Novartis, Basel Switzerland) barely improved dermatological lesions and pruritus in dogs with CAD. In contrast, the development of skin lesions in an experimental model of acute CAD in house dust mitesensitized dog was not prevented by the administration of hydroxyzine.In another study, it was demonstrated that cetirizine, a second-generation antihistamine, had no effect on pruritus after 14 days of administration in chronic CAD patients. Loratadine, cetirizine, and fexofenadine are commonly prescribed second-generation antihistamines. For optimal benefit, it is recommended that type I antihistamines be given either prior to a flare, or given to dogs with mild forms of CAD. Certain antihistamines (hydroxyzine, cetirizine, and cyproheptadine) may also block serotonin receptors. Some antihistamines modify behavior, notably, tricyclic antidepressants that include amitriptyline and doxepin. Adverse effects are often mild, largely being pruritus, but dry mouth, panting, sedation, drowsiness, hypersalivation, ataxia, trembling, hyperesthesia, and excitation have all been reported. Second-generation antihistamines should theoretically provide fewer side effects because they do not pass the blood–brain barrier, but this is not guaranteed. Despite all these negative data, in a study performed by Dell and collaborators, owners believe antihistamines to be an effective part of multimodal therapy for CAD. Benefits are only seen in a minority of dogs and benefits usually occur in the first 7–14 days of treatment. Antihistamines are better suited as an additive or used synergistically with other medications.Their lack of efficacy is probably linked to the fact that histamine is not the only molecule causing pruritis, as detailed in the immunopathology section.

抗组胺药对CAD的总体管理影响较小，但它们仍然是治疗CAD最常用的药物之一。I型口服抗组胺药包括羟嗪、苯海拉明、氯苯那敏、氯马斯汀和双咪替丁。其主要作用机制被认为是通过阻断组胺H1受体来干扰组胺介导的瘙痒。组胺是由几种细胞(如肥大细胞和嗜碱性粒细胞)释放的炎症介质，导致肥大细胞进一步脱颗粒和炎症细胞迁移，目前认为组胺通过增加神经元内的钙参与了无髓c纤维的兴奋，从而导致瘙痒。第一代抗组胺药可阻断组胺和毒蕈碱受体，并能够通过血脑屏障。第二代抗组胺药主要阻断组胺受体，通过血脑屏障的可能性较低。第一代抗组胺药研究的结果往往相互矛盾，但可以同意的是，结果通常微不足道或无效。一项随机对照试验报告，两种第一代口服抗组织胺，包括羟嗪/氯苯那敏组合和二甲茚定几乎没有改善CAD犬的皮肤病变和瘙痒。相反，在屋尘螨致敏犬的急性CAD实验模型中，羟嗪不能阻止皮肤病变的发生。在另一项研究中，第二代抗组胺药西替利嗪在慢性CAD患犬中使用14天后对瘙痒无影响。氯雷他定、西替利嗪和非索非那定是常用的第二代抗组胺药。为了达到最佳疗效，建议在发作前给予I型抗组胺药，或给予患有轻度CAD的犬。某些抗组胺药(羟嗪、西替利嗪和赛庚啶)也可能阻断5 -羟色胺受体。一些抗组胺药可改变行为，尤其是包括阿米替林和多塞平在内的三环类抗抑郁药。不良反应通常轻微，主要是瘙痒，但口干、喘息、镇静、嗜睡、过度兴奋、共济失调、颤抖、感觉过敏和兴奋均有报告。第二代抗组胺药由于不能通过血脑屏障，理论上应提供较少的副作用，但不能保证这一点。尽管有这些负面数据，但在Dell及其合作者进行的一项研究中，犬主人相信抗组胺是多模式治疗CAD的有效部分。仅在少数犬中观察到获益，且获益通常发生在治疗的前7-14天。抗组胺药更适合作为添加剂或与其他药物协同使用。它们缺乏疗效可能与以下事实有关:组胺不是引起瘙痒的唯一分子，详见免疫病理部分。

 

Glucocorticoids have powerful immunologic and anti-inflammatory activities. They exhibit many inhibitory effects directly acting on target genes, subsequently affecting the production of inflammatory mediators as well as induction of anti-inflammatory cytokines and thereby modulating cell-mediated and humoralimmunity.Glucocorticoids are effective and work quickly, but without proper management, undesirable adverse effects can occur. Typically, oral glucocorticoids are used for managing CAD. Oral prednisolone, prednisone, and methylprednisolone are given at 0.5–1 mg/kg per day.Adverse effects are generally proportional to steroid potency, dosage, and administration duration. Long-term control of CAD is best accomplished with alternate days of glucocorticoid therapies, at once every 48 hour or 72-hour dosing, to diminish side effects. Side effects include varying degrees of hypercortisolism-polydipsia, polyuria, polyphagia, weight gain, calcinosis cutis, dermal atrophy, pyoderma, panting, urinary tract infections, distended abdomen, depression, and diarrhea.

糖皮质激素具有强大的免疫和抗炎活性。它们表现出许多直接作用于靶基因的抑制作用，进而影响炎症介质的产生和抗炎细胞因子的诱导，从而调节细胞介导的免疫和体液免疫。糖皮质激素有效且起效迅速，但如果没有适当的管理，可能会发生不良反应。通常，口服糖皮质激素用于治疗CAD。口服泼尼松龙、泼尼松和甲泼尼龙的剂量为每天0.5-1 mg/kg。不良反应通常与类固醇的效力、剂量和给药持续时间成正比。长期控制CAD的最佳方式是隔日给予糖皮质激素治疗，每48小时或72小时给药一次，以减少副作用。副作用包括不同程度的皮质醇增多症——多饮、多尿、多食、体重增加、皮肤钙质沉着、皮肤萎缩、脓皮病、喘息、尿路感染、腹胀、抑郁和腹泻。

 

Cyclosporine is an immunosuppressive drug that was originally developed to prevent organ transplant rejection. It is desired for its immunosuppressive benefits compared to its low cytotoxicity effects and does not interfere with the results of intradermal skin tests. Cyclosporine inhibits intracellular calcineurin, which is a serine/threonine protein phosphatase involved in activation of T cells. The enzyme dephosphorylates nuclear factor of the transcription factor called “nuclear factor of activated T cell cytoplasmic” (NFATc). Transcription factors function by translocation to the nucleus with subsequent binding to the promoter of a gene, inducing its transcription, which in case of NFATc includes interleukin-2 (IL-2), an important cytokine for T cell activation and proliferation. By blocking calcineurin, dephosphorylation and subsequent translocation of NFATc is blocked, decreasing IL-2 release and therefore T cell activation. Cyclosporine has been extensively used to treat CAD and many other diseases; its advantageous effects extend beyond IL-2 suppression as cyclosporine affects canine keratinocytes, potentially cutaneous dendritic cells, inhibits mast cell degranulation, and innate immunity.69,85 Different cyclosporine formulations are available: veterinary, human brand-named, and generic formulations. Microemulsified formulations are preferred, as the microemulsion concentration is absorbed quickly and effectively through the gastrointestinal tract of dogs. The problem with cyclosporine is variability in its bioavailability, between dogs and even in the same dog. Presence of food in the gastrointestinal tract can play a role in making bioavailability even more variable, especially when food is high in fat, so it was recommended to administer ultramicronized cyclosporine 2 hours before or after feeding. Conversely, a study demonstrated that food did not have any impact on the efficacy of ultramicronized cyclosporine clinically. At CAD specific dosing (5mg/kg PO per day), common side effects include vomiting, diarrhea, and anorexia. Less frequently observed side effects include hypertrichosis, gingival hyperplasia, papillomatosis, and psoriasiform lichenoid dermatosis.There is often delayed gratification as it may take 4 weeks of therapy to see optimal clinical responses. The authors recommend prescribing name-brand veterinary formulations of cyclosporine at the optimal dosing daily until remission is achieved before tapering to the lowest effective dose or using modified versions. In most cases, this includes daily administration for 1 month before tapering. Cyclosporine is metabolized in the liver and intestines, by the cytochrome P450 isoenzymes, specifically CYP3A4. Drugs inhibiting or inducing cytochrome P-450 may affect cyclosporine metabolism. CYP3A4 inducers, for example rifampin or carbamazepine, may decrease cyclosporine levels by increasing their clearance. On the other hand, P-450 inhibitors, most notably several antifungal drugs (ketoconazole, itraconazole, and fluconazole), decrease cyclosporine clearance and increase cyclosporine concentration.Some clinicians take advantage of this by combining cyclosporine with ketoconazole. When used in combination, cyclosporine can be reduced to 2.5 mg/kg PO per day, but note that this is a calculated hypothesis and true dosing would vary individually. While this is a method to decrease cyclosporine, the authors see a higher incidence of adverse effects and each patient's bioavailability is variable so the reduction serves only as a guide. Some clinicians use trough and peak cyclosporine levels to provide guidance.

环孢素是一种免疫抑制药物，最初开发用于预防器官移植排斥反应。与低细胞毒性作用相比，它具有免疫抑制作用，并且不干扰皮内试验的结果。环孢素抑制细胞内钙调神经磷酸酶，钙调神经磷酸酶是一种丝氨酸/苏氨酸蛋白磷酸酶，参与T细胞的活化。这种酶将被称为“活化T细胞胞质核因子”(NFATc)的转录因子的核因子去磷酸化。转录因子的功能是通过转位到细胞核，随后结合到基因的启动子，诱导其转录，在NFATc中包括白细胞介素-2 (IL-2)，它是T细胞活化和增殖的重要细胞因子。通过阻断钙调神经磷酸酶，NFATc的去磷酸化和随后的转位被阻断，减少IL-2的释放，从而减少T细胞的活化。环孢素已被广泛用于治疗CAD等多种疾病;环孢素的优势作用超出了IL-2抑制，因为环孢素影响犬角质形成细胞，潜在影响皮肤树突状细胞，抑制肥大细胞脱颗粒和固有免疫。目前有不同的环孢素剂型:兽医剂型、人类品牌剂型和仿制剂型。首选微乳化制剂，因为微乳化浓度可快速有效地通过犬的胃肠道吸收。环孢素的问题是其生物利用度在不同犬之间，甚至在同一只犬身上的多变性。胃肠道中食物的存在会使生物利用度的变化更大，尤其是当食物含有高脂肪时，因此建议在进食前或进食后2小时给予超微环孢素。相反，有研究表明，食物对超微粒化环孢素的临床疗效没有任何影响。在CAD特定剂量(每日5mg/kg PO)下，常见的副作用包括呕吐、腹泻和厌食。较少观察到的副作用包括多毛症、牙龈增生、乳头瘤病和银屑病样苔藓样皮肤病。通常存在延迟效果，因为可能需要4周的治疗才能看到最佳的临床反应。作者建议以每日最佳剂量开出环孢素的名牌兽医制剂，直至达到缓解，然后逐渐减少至最低有效剂量或使用改良剂型。在大多数病例中，这包括每日给药1个月后逐渐减量。环孢素在肝和肠内通过细胞色素P450同工酶，特别是CYP3A4进行代谢。抑制或诱导细胞色素P-450的药物可影响环孢素的代谢。CYP3A4诱导剂(例如利福平或卡马西平)可能通过增加环孢素的清除率来降低环孢素水平。另一方面，P-450抑制剂，尤其是几种抗真菌药(酮康唑、伊曲康唑和氟康唑)，会降低环孢素清除率并增加环孢素浓度。一些临床医师利用这一点，将环孢素与酮康唑联用。当联合使用时，环孢素可减少到每天2.5 mg/kg PO，但请注意，这是一个计算的假设，真实剂量将因病例而异。虽然这是一种降低环孢素的方法，但作者发现不良反应的发生率较高，而且每个患犬的生物利用度是的，因此减少环孢素的剂量仅作为指导。一些临床医师使用环孢素的谷值和峰值水平来提供指导。

 

Oclacitinib (Apoquel®, Zoetis, Parsippany-Troy Hill, NJ) is an immune-modulating drug that inhibits the JAK/STAT signaling pathway. As previously mentioned, this pathway plays a major role in Th2 mediated inflammatory responses. It has been approved for treating pruritus related to allergic dermatitis, including CAD. Oclacitnib has been popular among clinicians for its high degree of efficacy, rapid onset, and like cyclosporine, no interference with intradermal skin testing, and low degree of adverse effects. The labeled prescribed dosing is 0.4–0.6 mg/kg PO every 12 hours for up to the 14 days and then once daily for maintenance according to manufacturer’s instructions. However, the authors find that most cases do not require this induction dosing. Oclacitinib allows comparable reduction in pruritus and clinical signs, compared to prednisolone, and outperforms cyclosporine in pruritus resolution and speed of action. Side effects, mainly gastrointestinal signs, are rare. Skin infections are also noted as side effects, but dogs with CAD tend to develop recurrent skin infections without medications. At the label dose, changes in hematological and serum chemical parameters have been described, but are minimal, including slight leukopenia, mild hypercholesterolemia, and minor increases in alkaline phosphatase (ALP) activity levels. Apoquel® should not be administered in dogs less than 12 months of age, nor in dogs with serious infections, such as pneumonia. Apoquel may exacerbate neoplastic conditions or increase susceptibility to infection, notably demodicosis. There is now a chewable formulation available for dogs.

奥拉替尼是一种抑制JAK/STAT信号通路的免疫调节药物。如前所述，该通路在Th2介导的炎症反应中起主要作用。已被批准用于治疗与过敏性皮炎(包括CAD)相关的瘙痒。奥拉替尼因疗效高、起效快、与环孢素类似、不干扰皮内试验、不良反应程度低而受到临床医生的青睐。标注的处方剂量为每12小时0.4-0.6 mg/kg PO，持续14天，然后根据制造商的说明每日1次用于维持。然而，作者发现大多数病例不需要这种诱导剂量。奥拉替尼在减轻瘙痒和临床症状方面与泼尼松龙相当，并且在瘙痒消退和作用速度方面优于环孢素。副作用，主要是胃肠道症状，少见。皮肤感染也被认为是副作用，但患有CAD的犬在没有药物治疗的情况下往往会出现反复的皮肤感染。在标签剂量下，血液学和血清化学参数发生了变化，但变化很小，包括轻度白细胞减少、轻度高胆固醇血症和碱性磷酸酶(ALP)活性水平轻度升高。爱波克不能用于年龄小于12个月的犬，也不能用于有严重感染(如肺炎)的犬。爱波克可能会加剧肿瘤或增加感染的易感性，尤其是蠕形螨病。现在有一种适合犬的咀嚼配方。

 

Lokivetmab (Cytopoint®, Zoetis, Parsippany-Troy Hill, NJ) is indicated for the treatment of clinical ailments of CAD. It is a caninized anti-interleukin (IL)-31 monoclonal antibody that was designed to neutralize IL-31, which is a cytokine acting on sensory neurons in the skin causing neuroinflammation and itch. It is commercially available as a subcutaneous injection in 1 ml vials containing 10, 20, 30, or 40 mg of lokivetmab. The recommended minimum dose is 1 mg/kg bodyweight once a month. Contraindications include not using in cases of hypersensitivity and dogs that weigh less than 3 kg, according to manufacturer’s instructions. In a study of 274 CAD dogs, lokivetmab administered at about once monthly dosing of 1 mg/kg, provided pruritic relief within a day, lasting duration, and all with a good safety profile. Another study confirmed the same findings.A recent 2021 study found that a single subcutaneous injection of 2 mg/kg suppressed pruritus within 3 hour for forty-two days; however, this study was performed with purpose bred Beagles. In a study performed by Marsella and collaborators comparing prednisone,oclactinib, cyclosporine, and lokivetmab for treatment of CAD in which dogs were challenged twice weekly with allergens, lokivetmab could be applicable in preventing flares and improving Transepidermal Water Loss (TEWL).

洛基维特单抗用于治疗CAD的临床疾病。它是一种犬化的抗白细胞介素(IL)-31单克隆抗体，旨在中和IL-31，而IL-31是一种作用于皮肤感觉神经元并引起神经炎症和瘙痒的细胞因子。市售的洛基维特单抗为1 ml小瓶皮下注射，内含10、20、30或40 mg洛基维特单抗。推荐的最低剂量为每月1次，每次1 mg/kg体重。根据制造商的说明，禁忌症包括不用于体重低于3公斤的过敏症患犬。在一项对274只CAD犬进行的研究中，洛基维特单抗以1 mg/kg的剂量每月给药1次，可在一天内缓解瘙痒，持续时间长，且所有这些都具有良好的安全性。另一项研究证实了同样的发现。2021年最近的一项研究发现，单次皮下注射2 mg/kg在3小时内抑制瘙痒42天;然而，这项研究是在有意饲养的比格犬上进行的。Marsella及其合作者进行了一项研究，比较了泼尼松、奥拉替尼、环孢素和洛基维特单抗治疗CAD的效果，在这项研究中，犬每周2次接受过敏原激发，洛基维特单抗可用于预防发作和改善经表皮失水率(TEWL)。

 

Pentoxifylline is a methylxanthine derivative that produces diverse physiological changes at the cellular level, such as white blood cell kinetics (responsiveness and activity), and platelet deformability and aggregation. It is used for a variety of inflammatory diseases. In a study performed by Singh and collaborators, pentoxifylline only provided low-quality evidence for the management of CAD. Pentoxifylline is available in a 400 mg coated tablet and dosing recommendations range between 20 and 30 mg/kg orally every 8–12 hours. Caution regarding the bioavailability of generic drugs ranging from 25% to 75%. Favorable response is not seen until 1–3 months of taking this drug. In general, serious side effects are not reported. Vomiting and diarrhea are seen infrequently. Dizziness and headaches have been reported in humans.

己酮可可碱是一种甲基黄嘌呤衍生物，可在细胞水平产生多种生理变化，如白细胞动力学(反应性和活性)以及血小板的变形性和聚集性。用于多种炎症性疾病。在Singh及其合作者进行的一项研究中，己酮可可碱仅为CAD的管理提供了低质量证据。己酮可可碱有一种400 mg包衣片剂，建议剂量范围为每8-12小时口服20 - 30 mg/kg。对25% ~ 75%的非专利药的生物利用度要谨慎。服用该药1-3个月后才观察到良好反应。一般而言，未报告严重的副作用。呕吐和腹泻少见。在人类中曾有头晕和头痛的报道。

 

Topical Active Ingredients

外用有效成分

Antipruritics

抗瘙痒

Topical steroids are the mainstay of CAD topical treatments and are popular for their ability to quickly reduce inflammation and pruritus, ability to treat focal areas, and rarely produce undesired side effects in the short term. Topical glucocorticoids interfere with the inflammatory cascade and pruritogenic pathway by impeding the arachidonic acid pathway, some inflammatory cytokines, and growth factors and decreasing some adhesion molecules expression. Glucocorticoids come in varying degrees of potency and different formulations and should be considered when formulating a treatment plan. In North America, topical glucocorticoids are divided into seven classes based on their ability to cause blanching (vasoconstriction). Mild glucocorticoids (classes 6 and 7) are preferred when lesions are mildly inflamed, large areas to be treated, or thin skin at site of application (glabrous regions). These classes are preferred for long-term use. Ointments have an occlusive nature and improve glucocorticoid absorption but may also macerate in occluded areas (skin folds, high hair density, and interdigital spaces). Creams are mixes of water suspended in oil. They are usually moisturizing and cosmetically acceptable but are generally less potent than ointments. Whatever delivery vehicle is chosen, it is not generally recommended that a topical steroid be applied more than twice a day. Hydrocortisone was the first to be used and is most commonly found in commercial formulations. Previous studies have noted adrenal suppression in formulations containing betamethasone, triamcinolone, and fluocinonide. When choosing a steroid, it is best to choose a less potent steroid such as hydrocortisone 1% or a soft steroid to avoid overuse causing undesirable side effects. Soft steroids include a new generation of diester topical glucocorticoids: hydrocortisone aceponate, mometasone furoate, and prednicarbate. These are metabolized at skin level into inactive ingredients, thereby dramatically reducing unwanted systemic effects. Triamcinolone acetonide and betamethasone are typically found in veterinary prescribed formulations of topical glucocorticoids. These are moderate-tohigh potent glucocorticoids, and side effects are common with misuse. In the United States, triamcinolone acetonide is commonly found as a cream or ointment and combined with neomycin and nystatin and betamethasone is found as a topical spray combined with gentamicin. Triamcinolone acetonide spray (Genesis®; Virbac, Carros, France) has been shown to be very efficacious in the treatment of CAD if applied for 4 weeks then tapered in the absence of clinical adverse effects. Of note, there is a commonly used product in the United States that contains neomycin sulfate, isoflupredone acetate, and tetracaine hydrochloride (Neo-predef®; Zoetis, Parsippany-Troy Hills, NJ). It is popular for desired effects of drying out moist lesions, but owners should be counseled as even mild overuse can quickly lead to undesired adverse effects. For all glucocorticoids, caution should be taken when applying on glabrous regions of the body, notably the abdomen, because undesired effects of dermal atrophy, scaling, comedones, or even calcinosis cutis, can occur quickly and most commonly in those locations.

外用类固醇是CAD外用治疗的主要方法，因其能够快速减轻炎症和瘙痒、治疗局部区域，并且很少在短期内产生不良副作用而受到欢迎。外用糖皮质激素通过阻碍花生四烯酸途径、一些炎症细胞因子和生长因子以及降低一些黏附分子的表达来干扰炎症级联反应和致痒通路。糖皮质激素有不同程度的效力和不同的剂型，制定治疗计划时应予以考虑。在北美，外用糖皮质激素根据其引起变白(血管收缩)的能力分为7类。当皮肤病变轻度炎症、需要治疗的面积大或用药部位皮肤薄(无毛区域)时，首选轻度糖皮质激素(6类和7类)。这些类别是长期使用的首选。软膏具有闭塞性，可改善糖皮质激素吸收，但也可能在闭塞区域(皮肤皱褶、毛发密度高和指间间隙)浸渍。面霜是水悬浮在油中的混合物。它们通常是保湿和化妆品可接受的，但通常不如药膏有效。无论选择何种给药方式，一般不建议局部外用类固醇应用超过一天两次。氢化可的松是最早使用的，最常在商业制剂中发现。之前的研究已经注意到含有倍他米松、曲安奈德和氟氟奈德的制剂对肾上腺有抑制作用。在选择类固醇时，最好选择威力较小的类固醇，如氢化可的松1%或软性类固醇，以避免过度使用造成不良副作用。软类固醇包括新一代二酯类外用糖皮质激素:丙酮酸氢化可的松、糠酸莫米松和泼尼卡酯。这些物质在皮肤水平被代谢成非活性成分，从而大大减少不必要的全身效应。曲安奈德和倍他米松通常出现在兽医处方的外用糖皮质激素制剂中。这些是中至高效力的糖皮质激素，误用时常见副作用。在美国，曲安奈德常被发现为乳膏或软膏，与新霉素和制霉菌素联用，有倍他米松与庆大霉素联用的外用喷雾剂。曲安奈德喷雾剂已被证明在治疗CAD时非常有效，如果应用4周后逐渐减量，并且没有临床不良反应。值得注意的是，在美国有一种常用产品含有硫酸新霉素、醋酸异氟泼酮和盐酸丁卡因。它很受欢迎，因为它可以干燥潮湿的皮肤病变，但应该提醒宠主，即使是轻微的过度使用也会很快导致不希望的不良影响。对于所有糖皮质激素，在机体无毛部位(尤其是腹部)使用时均应谨慎，因为皮肤萎缩、皮屑、粉刺甚至皮肤钙质沉着症等不良效应可能很快发生，且最常见于这些部位。

 

Pramoxine hydrochloride is a topical anesthetic and is used as an antipruritic. It is an effective surface anesthetic and is well tolerated by skin and mucous membranes with extremely low rates of toxicity. Pramoxine exerts its anesthetic and anti-pruritic effect by preventing excitation of slow C fibers that signal itch and pain. This is achieved by reversibly binding voltage-gated sodium channels preventing membrane depolarization, and subsequently inhibiting the generation of action potentials in these peripheral neurons. Rarely, contact reactions are seen. One crossover open clinical trial evaluated two formulations of pramoxine cream rinse and concluded that after 4 weeks, there was at least 50% reduction in pruritus from 41% of the owners and antipruritic effects lasted 48 hour. Unfortunately, with frequent and repeated use, duration of effect and efficacy wanes. In veterinary medicine, it is usually found in the form of a shampoo, rinse, and spray and often in combination with ceramides or hydrocortisone, and combination formulations serve dual moisturizing and antipruritic effects.

盐酸普莫卡因是一种局部麻醉剂并用作止痒药。是一种有效的表面麻醉剂，皮肤和黏膜耐受性良好，毒性极低。普莫卡因通过阻止发出瘙痒和疼痛信号的慢C纤维兴奋来发挥其麻醉和止痒的作用。这是通过可逆地结合电压门控钠通道，防止膜去极化，随后抑制这些外周神经元动作电位的产生来实现的。接触反应很少出现。一项交叉开放临床试验评估了两种配方的普莫卡因乳膏冲洗液，结果表明4周后，41%的患犬瘙痒至少减轻了50%，且止痒效果持续48小时。遗憾的是，随着频繁和重复使用，效果和疗效的持续时间会减少。在兽医学中，它通常以香波、浸渍剂和喷雾的形式存在，通常与神经酰胺或氢化可的松结合在一起，组合配方具有双重保湿和止痒的效果。

 

Tacrolimus has been explored for the treatment of localized lesions of atopic dogs. Three studies have concluded that although expensive, tacrolimus is promising for managing localized CAD lesions with nominal side effects. Most dogs were able to reduce at least 50% of clinical signs from baseline after 4- to 12-week treatments. Adverse effects of mild irritation were noted in a minority of cases: 0.1% ointment formulation is recommended due to 0.3% tacrolimus causing a fourfold increase in serum tacrolimus concentrations.

他克莫司已被探索用于治疗特应性皮炎犬的局部病变。三项研究得出的结论是，虽然价格昂贵，但他克莫司在治疗局部CAD病变方面很有前景，且副作用很小。经过4 ~ 12周的治疗，大多数犬的临床症状较基线至少减轻了50%。少数病例出现轻微刺激的不良反应:建议使用0.1%软膏配方，因为0.3%他克莫司会使血清他克莫司浓度增加4倍。

 

Emollients and Moisturizers

润肤剂和保湿剂

Since CAD patients have skin barrier defects, replenishing the oils can be beneficial in controlling clinical signs. Emollients are vehicles that soften, lubricate, or soothe the skin. Moisturizers aide by reducing TEWL via hygroscopic molecules or blocking agents. There are many options:

由于CAD患犬存在皮肤屏障缺陷，补充油脂有助于控制临床症状。润肤剂是软化、润滑或舒缓皮肤的工具。润肤霜通过吸湿分子或阻断剂来减少经皮水分流失。有很多选择:

 

Fatty acids are important in hydration and serving as a barrier in controlling TEWL. Commercial products are direct topical applications of fatty acids to the skin. Dermoscent Essential 6® Spot-on (Nextmune, Phoenix, AZ) contains a combination of fatty acids and emollients that restore hydrolipidic film on the skin, maintain hydration, and maintain epidermal barrier function. In addition, inflammation is controlled with antioxidant and anti-free radicals. There have been several studies proving the efficacy of these essential fatty acids in reducing TEWL and pruritus scores with no side effects. An induction dosing of one pipette every week for 2 months followed by maintenance dosing of one pipette every 2 weeks for as long as necessary according to manufacturer’s instructions. No massage is required, and it is recommended not to bathe 2 days before and after application. The amount of product per pipette depends on the size of the pet: up to 10 kg, 10–20 kg, and 20– 40 kg. The fragrance is a fresh herbal scent. Another product, Atopivet® Spot-on (Dechra, Cheshire, CT) contains Biosfeen®, a sphingomyelin-rich sphingolipid, and Dermial®, a glycosaminoglycan, specifically hyaluronic acid. The fragrance is a lavender scent. It comes in 2mL pipettes and can be applied to affected areas or between the shoulder blades and down the back twice weekly for at least 5–8 weeks before modifying the application as needed. It also comes in a mousse and skin care collar. The collar only contains Biosfeen® and can help the skin barrier for up to 2 months.

脂肪酸在水合作用中很重要，并可作为控制经皮水分流失的屏障。商业产品是直接外用脂肪酸到皮肤。Dermoscent Essential 6®滴剂包含脂肪酸和润肤剂的组合，恢复皮肤上的水脂膜，维持水分，维持表皮屏障功能。此外，炎症是由抗氧化剂和抗自由基控制的。已有多项研究证明，这些必需脂肪酸可有效降低经表皮失水率和瘙痒评分，且无副作用。每周给予1支滴剂诱导给药，持续2个月，之后根据制造商的说明书，每2周给予1支滴剂维持给药，必要时持续给药。不需要按摩，建议在使用前两天和使用后两天不要洗澡。每个滴剂的产品量取决于宠物的大小:小于10公斤，10 - 20公斤，和20 - 40公斤。这是一种新鲜的草本香味。另一种产品是Atopivet®滴剂，它含有生物脂(Biosfeen®），一种富含鞘磷脂的鞘脂，和dermal®(一种糖胺聚糖，特别是透明质酸)。这是薰衣草的香味。它有2mL的滴剂，可以应用于患病区域或肩胛骨之间和下背部每周两次，至少5-8周，然后修改应用程序的需要。它也有一个摩丝和护肤项圈。该项圈只含Biosfeen®，可以帮助皮肤屏障长达2个月。

 

Coconut oil has been a very popular remedy with self-directed owners in recent years. Virgin coconut oil is preferred since it is colorless, odorless, and cosmetically elegant, and has antibacterial activity. For coconut oil to be clinically effective, it must be applied twice daily for at least 4 weeks. This was adapted from human literature, and for dogs, the challenge is reaching skin level with hair being a barrier.

近年来，椰子油在自我指导的宠主中是一种非常受欢迎的疗法。维京椰子油是首选，因为它无色，无味，美容优雅，并具有抗菌活性。为了使椰子油在临床上有效，必须每天应用两次，至少使用4周。这是根据人类文学改编的，对犬来说，挑战是达到皮肤水平，而毛发是一个障碍。

 

Mineral oil/liquid paraffin (highly refined mineral oil) baths also aid in reducing TEWL. In this protocol, the first step is to bathe the patient with a shampoo. The chosen shampoo should be decided based on the patient’s presentation. If a patient tends to present with secondary infections, then an antiseptic shampoo should be recommended. If the patient tends to present with scale, then the clinician can prescribe a keratolytic or keratoplastic shampoo. It may be prudent to warn the client that for the first couple of baths, alopecia may be expected from dislodging affected hairs. The second step is to formulate a 50:50 mixture of water and mineral oil. This step replaces the lipid matrix of the stratum corneum. Soak the patient for 1 hour, to allow the oils to penetrate. In the final step, the patient should be washed with dishwashing soap to break down excess oils. Another option is to use large puppy pads to soak up the excess oil. The authors prefer the brands Alpha Keri and Patterson Medical unscented paraffin oil.

矿物油/液体石蜡(高度精炼的矿物油)浴也有助于减少经皮水分流失。在该方案中，第一步是用香波给患犬洗澡。选择的香波应根据患犬的表现来决定。如果患犬倾向于出现继发感染，则应建议使用抗菌香波。如果患犬倾向于出现皮屑，那么临床医师可以开出角质溶解剂或角质促成剂香波。谨慎地提醒患犬，在最初的几次沐浴中，可能会因毛发脱落而出现脱毛。第二步是将水和矿物油配制成50:50的混合物。这一步取代了角质层的脂质基质。浸泡患犬1小时，让油脂渗透。最后一步，应该用洗碗皂清洗患犬，以分解多余的油脂。另一种选择是用大的小犬护垫来吸收多余的油。作者更喜欢Alpha Keri和Patterson Medical无味石蜡油。

 

Wet wrapping is a protocol adapted from human literature to control atopic eczema in children. This protocol is effective for rehydrating and calming the skin, as well as helping topical medications work better. Fill the bathtub with lukewarm water, then add liquid paraffin. Immerse the pet minus the head for 5 min. Remove the pet and pat (not rub) dry. Cover the skin with a thick moisturizer or emollient. For severely pruritic pets, mometasone furoate 0.1% ointment is advised on pruritic areas as this is a soft steroid and theoretically will not be absorbed systemically. Next, place fitted clothes and/or socks in hot water and wring them out, then dress the patient. Apply a second layer of fitted clothes and/or socks, leave on for 40 minutes or until the dressing is dry. Perform once daily until the patient is less pruritic or two to three times a week if steroids are used. Clients will commonly need to make adjustments to the fitted clothes and socks for desired effects. Socks should extend to above the second joint to avoid slippage. Human studies have repeatedly demonstrated the efficacy of wet wrapping with topical corticosteroids, resulting in an improved quality of life and avoiding systemic therapy. It is prudent to warn caretakers of this laborious and time-consuming task, but relief is almost immediate and can avoid systemic therapy.The authors often reach for this therapy for patients who have had adverse effects to systemic CAD medication.

湿裹方法是根据人类文献改编的控制儿童特应性湿疹的方案。这种方法可以有效地为皮肤补水和镇静，并帮助局部药物更好地发挥作用。将浴缸装满温水，然后加入液体石蜡。将宠物头部浸泡5分钟。取出宠物，轻拍(而不是揉搓)干燥。用厚厚的保湿霜或润肤剂覆盖皮肤。对于严重瘙痒的宠物，建议在瘙痒部位使用糠酸莫米松0.1%软膏，因为这是一种软性类固醇，理论上不会被全身吸收。接下来，将合身的衣服和/或袜子放在热水中拧干，然后给患犬穿上衣服。涂上第二层合身的衣服和/或袜子，静置40分钟或直到敷料干燥。每日1次，直至患犬瘙痒减轻;如果使用类固醇，则每周2 ~ 3次。客户通常需要调整合身的衣服和袜子，以达到预期的效果。袜子应该延伸到第二个关节以上，以避免滑动。人体研究已多次证明外用皮质类固醇湿敷的疗效，可改善生活质量，避免全身治疗。谨慎的做法是提醒护理人员注意这项费时费力的工作，但症状几乎可以立即缓解，并且可以避免全身治疗。作者通常将这一疗法用于对全身性CAD药物有不良反应的患犬。

 

Nutrition

营养

The most important essential fatty acids (EFAs) in cutaneous homeostasis in dogs are linoleic acid (18:2N-6) and alpha-linoleic acid (18:3N-3). The proposed mechanism of how EFAs function in controlling pruritus includes inhibition of arachidonic acid metabolism in favor of dihomo-gamma-linolenic acid (DGLA). The final product of DGLA metabolism is prostaglandin E1, which is thought to have anti-inflammatory effects. There are unsatisfactory evidence-based studies supporting the use of EFAs; ultimately, results depend on the source, amount, and duration of supplementation. It has been proposed that an adequate therapeutic trial might necessitate 3–4 months of use and that EFAs may have a steroid sparing effect. Side effects are rarely reported but can consist of vomiting, diarrhea, weight gain, unpleasant odor, or “fish breath”.

在犬的皮肤稳态中最重要的必需脂肪酸是亚油酸(18:2N-6)和α -亚油酸(18:3N-3)。目前提出的EFA控制瘙痒的机制包括抑制花生四烯酸代谢，支持二高- γ -亚麻酸(DGLA)。DGLA代谢的最终产物是前列腺素E1，被认为具有抗炎作用。支持使用EFA的循证研究并不令人满意;最终，结果取决于补充的来源、数量和持续时间。有人提出，充分的治疗试验可能需要使用3-4个月，而且EFA可能有减少类固醇用量的作用。副作用很少有报道，但可能包括呕吐、腹泻、体重增加、难闻的气味或“鱼腥气”。

 

Probiotics have recently gained attention. Many studies have shown a significant and synergistic connection between the gastrointestinal and dermatological systems, and scientific evidence link gastrointestinal homeostasis to cutaneous manifestations. Knowledge as to the exact mechanisms of the link are still being investigated, but it is thought that interactions between the microbiome and the intestinal immune system results in modulation of immunity with effects on many other systems beyond the gut. Many skin diseases, including atopic dermatitis, seem to be related to gut dysbiosis. Modulation of canine intestinal microbiota is getting more attention as a taking part of multimodal CAD management. The exact mechanism of action of probiotics still needs further investigation, but like immunotherapy, it appears that the immune response might shift towards a Th1 mediated response, instead of Th2, which is detrimental in AD.In a recent study, probiotics played a role in CAD management as a complimentary or steroid sparing therapy.

益生菌最近受到了关注。许多研究表明，胃肠道和皮肤系统之间存在显著的协同关系，有科学证据表明胃肠道稳态与皮肤表现之间存在关联。关于这一联系的确切机制仍在研究中，但据认为，微生物组和肠道免疫系统之间的相互作用导致了免疫调节，并对肠道以外的许多其他系统产生影响。包括特应性皮炎在内的许多皮肤病似乎与肠道菌群失调有关。犬肠道菌群的调节作为多模式CAD管理的一部分受到越来越多的关注。益生菌的确切作用机制仍需进一步研究，但与免疫治疗一样，似乎免疫应答可能向Th1介导的反应转变，而不是Th2，这对AD是有害的。在最近的一项研究中，益生菌作为补充或减少类固醇的疗法在CAD治疗中发挥了作用。

 

Zinc plays a role in skin health and proper immune function and in the management of some skin diseases. In a 24-week, randomized, double-blinded controlled crossover study with 27 dogs, atopic dogs receiving glucocorticoids and zinc methionine supplementation may benefit in both clinical response and pruritus levels. Vitamin D has been a hot topic as part of multimodal therapy for many diseases including atopic dermatitis.

锌在皮肤健康和适当的免疫功能中发挥作用，并在一些皮肤病的管理中发挥作用。在一项为期24周的随机双盲对照交叉研究中，27只犬接受糖皮质激素和蛋氨酸锌补充治疗，可能在临床反应和瘙痒水平方面都有益。作为特应性皮炎等多种疾病综合治疗的一部分，维生素D已成为研究的热点。

 

Vitamin D is involved with skin barrier function and immune response, including the production of antimicrobial peptides. It has been associated with severe allergic diseases in humans, but the role of vitamin D in CAD is still in development. It has been shown that CAD has been associated with low vitamin D and that supplementation CADESI and pruritus has been associated with increased serum levels. There is also evidence that canine mast cell tumor growth is inhibited by vitamin D because in one study, Labrador Retriever dogs with low vitamin D levels had an increased chance of developing mast- cell tumors. Overall, at this time, there is insufficient evidence to determine vitamin D’s role in the development or pathogenesis of CAD.

维生素D参与皮肤屏障功能和免疫应答，包括抗菌肽的产生。它与人类严重的过敏性疾病相关，但维生素D在CAD中的作用仍在研究中。已有研究表明，CAD与低维生素D相关，而补充与CADESI和瘙痒与血清水平增加相关。也有证据表明，维生素D可以抑制犬肥大细胞肿瘤的生长，因为在一项研究中，维生素D水平低的拉布拉多寻回犬患肥大细胞肿瘤的几率增加。总体而言，目前还没有足够的证据确定维生素D在CAD的发生或发病机制中的作用。

 

Palmitoylethanolamide PEA, a type of cannabinoid receptor agonist, has been used in CAD management as part of multimodal therapy. PEA-Cannabinoid receptors (CB1, CB2) are expressed on endothelial cells, mast cells, and canine keratinocytes. Immunohistochemical staining indicated increased cannabinoid receptors in the dermis of atopic dogs, compared to their healthy counterparts. Treatment with cannabinoid receptor agonists, such as Palmitoylethanolamide or PEA, has been shown to decrease mast cell degranulation, histamine-related pruritus, and vasodilation. It has also been demonstrated that skin levels of endogenous PEA are higher in atopic dogs.

十六酰胺乙醇是一种大麻素受体激动剂，已作为多模式治疗的一部分用于CAD的管理。PEA-大麻素受体(CB1、CB2)表达于内皮细胞、肥大细胞和犬角质形成细胞。免疫组织化学染色显示，特应性皮炎犬真皮中大麻素受体较健康犬增多。大麻素受体激动剂(如十六酰胺乙醇或PEA)治疗已被证明可减少肥大细胞脱颗粒、组胺相关瘙痒和血管舒张。也有研究表明，皮肤内源性PEA水平在特应性皮炎犬中较高。

 

In recent years, commercial diets aimed specifically for canine atopic dermatitis are available. Examples include Hill’s Derm Complete® and Royal Canin’s Skintopic®. Hill’s Derm Complete is an egg-based diet that has the HistaGuard Complex, which contains bioactives and phytonutrients that help reduce allergic response. Phytonutrients help decrease inflammatory cytokines, mast cell degranulation, and interfere with dendritic function and maturation. Royal Canin’s Skintopic features a patented Dermauxillium Complex, a unique blend of nutrients and antioxidants to aid in supporting skin and coat health. In a double-blinded placebo-controlled study, pVAS and CADESI-04 scores were improved by at least 30–50%, and drug-sparing effect could be observed within 3–6 months after starting the new diet.

近年来，有专门针对犬特应性皮炎的商业饮食。例如Hill 's Derm Complete®和Royal Canin 's Skintopic®。Hill 's Derm Complete®是一种以鸡蛋为基础的饮食，含有HistaGuard复合物，其中含有生物活性物质和植物营养素，有助于减少过敏反应。植物营养素有助于减少炎性细胞因子，肥大细胞脱颗粒，并干扰树突功能和成熟。Royal Canin 's Skintopic的特色是专利的Dermauxillium Complex，一种独特的营养和抗氧化剂的混合，帮助支持皮肤和被毛的健康。在一项双盲安慰剂对照研究中，pVAS和CADESI-04评分改善至少30-50%，并且在开始新饮食后3-6个月内可观察到药物节约效应。

 

Environmental Control

环境管理

Allergen avoidance should be considered whenever possible, although this is frequently difficult to accomplish. Bathing can help minimize cutaneous exposure as well as wiping the patient after outside exposure to minimize allergen exposure contact. Patients with pollen and plant allergies should not be outside when grass is mowed or on windy days. Ideally, inciting plants should be removed from the patient’s environment whenever possible. For house dust and molds, high efficiency particulate air (HEPA) filters air purifiers and frequent housekeeping should be implemented, such as increased frequency of vacuuming and changing bedding. Dogs should be removed from the property during these activities to limit exposure.

应尽可能地考虑避免过敏原，但这通常很难做到。洗澡有助于减少皮肤暴露，在室外暴露后擦拭有助于减少过敏原暴露接触。花粉和植物过敏患犬在割草或刮风的时候不应在室外。理想情况下，有刺激性的植物应尽可能从患犬周围的环境中清除。对于室内灰尘和霉菌，应使用高效微粒空气过滤器(HEPA)空气净化器和经常打扫卫生，例如增加吸尘和更换床上用品的频率。在这些活动期间，犬应该离开物体，以限制暴露。

 

Conclusion

结论

Considering the complexity of CAD pathophysiology, treatment needs to be on an individual basis, taking into consideration all factors, such as genetics, nutrition, and environment. However, further research is needed, as no treatment is 100% successful, and in some cases even with a combination of treatments, relief is not achieved. None of the current drugs are curative and will require lifelong use in some cases, putting a financial burden on patients or clients. There are many more therapeutics in the pipeline specifically in human medicine, which can translate to new therapies for dogs, albeit at a high cost, as many newer treatments are biologicals. Finding therapies that can successfully address the root cause and disrupt the cycle of insult and inflammation will require additional research and probably a wider approach looking at cells and pathways previously not investigated. With increased advances in technology, further elucidating the complex interactions of cells in the skin, this goal is achievable.

考虑到CAD病理生理的复杂性，治疗需要在个体化的基础上，综合考虑遗传、营养和环境等所有因素。然而，需要进一步研究，因为没有任何治疗是100%成功的，在某些病例中，即使联合治疗，也无法达到缓解。目前没有一种药物是治愈的，在某些病例需要终身使用，给患犬或客户带来了经济负担。有更多的治疗方法正在研发中，特别是在人类医学方面，这些方法可以转化为犬的新疗法，但费用很高，因为许多新的疗法都是生物疗法。要找到能够成功解决根本原因并打破损伤和炎症循环的疗法，需要进行更多的研究，可能还需要更广泛的方法，着眼于以前未研究过的细胞和通路。随着技术的不断进步，进一步阐明皮肤中细胞的复杂相互作用，这一目标是可以实现的。

 

 

 

 

 

Figure 1 Immunological pathways and relevant therapeutic interventions in the canine atopic skin. Several cell types are involved in inflammation in the skin, including keratinocytes, fibroblasts, dendritic cells, mast cells, several subpopulation of T lymphocytes and B lymphocytes. Different cytokines and other inflammatory mediators are released by various cells and can be targeted by topical and systemic therapeutics. Created with Biorender.com. Abbreviations: ILC, Innate lymphoid cells; IL, Interleukin; AMP, antimicrobial peptides; TSLP, thymic stromal lymphopoietin; IgE, immunoglobulin E.

图1犬特应性皮炎皮肤的免疫通路和相关治疗干预多种细胞类型参与皮肤炎症，包括角质形成细胞、成纤维细胞、树突状细胞、肥大细胞、T淋巴细胞和B淋巴细胞的几个亚群。各种细胞释放不同的细胞因子和其他炎症介质，并可作为外部和全身治疗的靶点。创建与Biorender.com。

缩写:ILC：固有淋巴样细胞;IL：白介素;AMP：抗菌肽;TSLP：胸腺基质淋巴细胞生成素;IgE：免疫球蛋白E。

谢尔顿

南海

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杨先生

王帆

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