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Evidence-base for the beneficial effect of nutraceuticals in canine dermatological immune-mediated inflammatory diseases — A literature review
营养品在犬皮肤免疫介导炎性疾病中优势的证据支持-文献综述
作者：Kelly van Amersfort | Annette van der Lee | Esther Hagen-Plantinga
翻译：王帆
Abstract
Background: Immune-mediated inflammatory diseases (IMIDs) are associated with an abnormal immune response, resulting in a disturbed homeostasis and chronic inflammation. Most canine dermatological IMIDs (cDIMIDs), such as allergies, autoimmune and immune-mediated diseases, require longterm treatment with immunosuppressive drugs with potential adverse effects. In general, nutraceuticals are thought to be safe. As a result, there is a tendency for the more frequent use of nutraceuticals in veterinary medicine.
Objectives: The aim of this review was to present evidence-based proof for the use of various nutraceuticals in the treatment of cDIMIDs and, where possible, to provide conclusions to guide their use in veterinary dermatological practice.
Methods: A comprehensive literature search on common cDIMIDs and nutraceuticals was performed. Only peer-reviewed articles published in English and related to the study topic were included. A total of 64 eligible publications were classified in five categories based on study design and substantively assessed on additional criteria such as standardisation of diets and number of included animals. For final appraisal, classification of major, minor or no evidence was used whereby efficacy was based on clinical outcome measurements.
Conclusions: Minor evidence for the beneficial use of several nutraceuticals, including essential fatty acids, niacinamide and probiotics, was found for treatment of specific cDIMIDs. These nutraceuticals may improve clinical signs or reduce the required dose of concurrent medication (e.g. drug-sparing effect) in some dogs. Some nutraceuticals also may be used for long-term maintenance therapy. Despite some promising findings, major evidence for the use of nutraceuticals in cDIMIDs is lacking, warranting further research.
摘要
背景: 免疫介导的炎性疾病(IMIDs)与异常的免疫反应相关，导致体内稳态紊乱和慢性炎症。大多数犬皮肤病IMID (cDIMID)，如过敏症、自体免疫和免疫介导疾病，需要使用具有潜在副作用的免疫抑制药物进行长期治疗。一般来说，营养品被认为是安全的。因此，有一种趋势是在兽医学中更频繁地使用营养剂。
目的: 本综述的目的是为治疗cDIMID的各种营养品提供循证证据，并在可能的情况下为其在兽医皮肤科临床中的使用提供指导。
方法: 常见的cDIMID和营养品进行全面的文献检索。仅包括以英文发表的与研究主题相关的同行评审文章。根据研究设计，共有64份合格出版物分为五类，并根据其他标准(如日粮标准化和纳入动物数量)进行了实质性评估。对于最终评估，使用主要、次要或无证据的分类，从而根据临床结果测量疗效。
结论和临床相关性: 发现少量证据表明，几种营养食品(包括必需脂肪酸、烟酰胺和益生菌)可用于治疗特定cDIMID。这些营养品可能会改善某些犬的临床症状，或减少同时用药所需的剂量(例如药物节约效应)。一些营养品也可用于长期维持治疗。尽管存在一些有前景的发现，但缺乏在cDIMID中使用营养品的主要证据，需要进一步研究。
KEYWORDS
关键词
canine atopic dermatitis, dietary supplements, essential fatty acids, immune system diseases, therapeutics
犬特应性皮肤病、膳食补充剂、必需脂肪酸、免疫系统疾病、治疗
INTRODUCTION
介绍
Immune-mediated inflammatory diseases (IMIDs) can be described as conditions whereby an immune dysregulation causes clinical signs of disease through various inflammatory cascades, disturbing homeostasis. The inflammatory process involves complex pathways and is a reaction of the immune system to injuries of various origin with the aim of restoring homeostasis. However, in IMIDs homeostasis of the individual usually remains disturbed due to continuing inflammation along with oxidative stress. As a result, further disruption of biological processes and cell and tissue damage is seen. Micronutrients such as vitamins and minerals play important roles in the proper functioning of the immune system. Deficiencies can further contribute to the disturbance of homeostasis and disease progression. For example, zinc deficiency is thought to be associated with infectious disease and impaired immune response.
免疫介导的炎性疾病(IMIDs)可以被描述为通过各种炎症级联反应，扰乱内稳态，引起临床症状的一种免疫失调性疾病。炎症过程涉及复杂的途径，是免疫系统对各种来源的病变的反应，目的是恢复内稳态。然而，在IMIDs中，由于持续的炎症和氧化应激，个体的内稳态通常仍然受到干扰。结果，出现进一步破坏生物过程和细胞和组织病变。维生素和矿物质等微量营养素在免疫系统的正常运作中发挥着重要作用。缺乏可进一步导致体内平衡紊乱和疾病进展。例如，锌缺乏被认为与传染病和免疫反应病变有关。
In the field of veterinary dermatology, examples of IMIDs are allergies, autoimmune diseases and other immune-mediated disorders such as symmetrical lupoid onychodystrophy. Many of these diseases have a chronic disease course, and for treatment, immunosuppressive drugs are most often required. In general, compared with most immunomodulatory drugs, nutraceuticals are thought to be safe. As a result, there is a tendency for the more frequent use of nutraceuticals in veterinary medicine, including in dermatology. The term nutraceutical is a conjunction of the words nutrition and pharmaceutical and can be defined as ‘any substance that may be considered a food or part of a food and provides medical or health benefits, including the prevention and treatment of disease’.
在兽医皮肤病学领域，IMIDs的例子是过敏症、自体免疫性疾病和其他免疫介导的疾病，如对称性狼疮样甲形成不良。这些疾病中有许多具有慢性病程，为了治疗，最常需要免疫抑制药物。一般来说，与大多数免疫调节药物相比，营养品被认为是安全的。因此，有一种趋势是在兽医学中更频繁地使用营养品，包括在皮肤科。营养品一词是营养和药品两个词的合成词，可以定义为“任何可以被认为是食品或食品的一部分，并提供医疗或健康益处，包括预防和治疗疾病的物质”。
When regarding canine dermatological IMIDs (cDIMIDs), commonly used nutraceuticals are vitamins A, B3, D and E, zinc and essential fatty acids (EFAs). In addition, palmitoylethanolamide (PEA) and probiotics have recently attracted interest. These nutrients play important roles in the skin and/or immune system, which may explain their potential beneficial role when used in IMIDs. Vitamins A and D and zinc are important for the proliferation and differentiation of keratinocytes. Vitamin A can also act as an antioxidant, and zinc and vitamin D have regulatory and enhancing effects in both the innate and adaptive immune system. Vitamin B3, also known as niacinamide, mostly is used in combination with tetracyclines due to a proposed synergistic effect. Both have anti-inflammatory effects, including downmodulation of cytokines,inhibition of leucocyte chemotaxis, matrix metalloproteinases (MMPs) and NF-ƙB, as well as inhibition of synthesis of pro-inflammatory cytokines.
对于犬皮肤IMIDs (cDIMIDs)，常用的营养品是维生素A、B3、D和E、锌和必需脂肪酸(EFAs)。此外，十六酰胺乙醇(PEA)和益生菌最近也引起了人们的兴趣。这些营养品在皮肤和/或免疫系统中发挥着重要作用，这可能解释了它们在IMIDs中使用时的潜在有益作用。维生素A、D和锌对角质形成细胞的增殖和分化很重要。维生素A也可以作为一种抗氧化剂，锌和维生素D对先天免疫系统和适应性免疫系统都有调节和增强作用。维生素B3，也被称为烟酰胺，因为有协同作用，主要是与四环素结合使用。两者都具有抗炎作用，包括下调细胞因子，抑制白细胞趋化性，基质金属蛋白酶(MMPs)和NF-ƙB，以及抑制促炎细胞因子的合成。
Niacinamide and vitamin D also play a role in epidermal skin barrier synthesis. Niacinamide is a key enzyme of the sphingolipid synthesis. Vitamin D is involved in synthesis and secretion of antimicrobial peptides. Vitamin D also is a regulator of genes involved in skin barrier function. Zinc is a component of finger proteins and MMPs, which are involved in expression of filaggrin and epidermal remodelling.
烟酰胺和维生素D也在表皮皮肤屏障的合成中发挥作用。烟酰胺是鞘脂合成的关键酶。维生素D参与抗菌肽的合成和分泌。维生素D也是皮肤屏障功能基因的调节因子。锌是指蛋白和基质金属蛋白酶的组成部分，参与聚丝蛋白和表皮重构的表达。
Vitamin E (alpha-tocopherol) is an important lipidsoluble antioxidant, protecting unsaturated fatty acids (FAs) in cell membranes from peroxidation. It also is thought to play a role in arachidonic acid (ARA) metabolism. Supplementation of vitamin E has been shown to improve immune responses by enhancing lymphocyte proliferation, protecting membranes of macrophages against oxidative damage, supporting cells during phagocytic activity and influencing production of cytokines and prostaglandins.
维生素E (α -生育酚)是一种重要的脂溶性抗氧化剂，保护细胞膜中的不饱和脂肪酸(FAs)免受过氧化作用。它也被认为在花生四烯酸(ARA)代谢中发挥作用。补充维生素E已被证明可以通过增强淋巴细胞增殖、保护巨噬细胞膜免受氧化病变、在吞噬活动期间支持细胞以及影响细胞因子和前列腺素的产生来改善免疫反应。
EFAs typically refer to -3 and omega-6 polyunsaturated FAs, which are essential as they cannot be synthesised de novo in the body. Consequently, precursors of the omega-3 and omega-6 families, respectively, alpha-linolenic (ALA) and linoleic acid (LA), need to be ingested through the diet. The body is able to convert these precursors into more complex omega-3 and omega-6 FAs, although this ability is limited.
脂肪酸通常指的是-3和-6多不饱和脂肪酸，它们是必需的，因为它们不能在体内从头合成。因此，omega-3和omega-6家族的前体，分别是α -亚麻酸(ALA)和亚油酸(LA)，需要通过饮食摄入。人体能够将这些前体转化为更复杂的-3和-6脂肪酸，尽管这种能力是有限的。
Some EFAs, such as eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and gamma-linolenic acid (GLA), exhibit anti-inflammatory properties. For example, they compete with ARA as precursor for the cyclooxygenase pathway, leading to fewer inflammatory cytokines, and also inhibit cytokine secretion and T-cell proliferation and activation. EFAs also play an important role in skin barrier homeostasis. In that respect, LA is particularly crucial as it is a precursor of ceramides, which are key components of the extracellular lipid matrix.
一些脂肪酸，如二十碳五烯酸(EPA)、二十二碳六烯酸(DHA)和γ-亚麻酸(GLA)，具有抗炎特性。例如，它们与ARA竞争作为环加氧酶途径的前体，导致炎症因子减少，也抑制细胞因子的分泌和T细胞的增殖和激活。EFAs在皮肤屏障稳态中也起着重要作用。在这方面，LA尤其重要，因为它是神经酰胺的前体，神经酰胺是细胞外脂质基质的关键成分。
The endogenous lipid molecule PEA is synthesised on demand by various cells and tissues in response to different stressful stimuli. PEA has been shown to exert three main effects: analgesia, inhibition of inflammation and cell protection via preservation of local homeostasis. The exact mechanism of action is not fully understood, although there are several hypotheses, including its role in the autacoid local inflammation antagonisms (ALIA) pathway, which impacts mast cell degranulation.
内源性脂质分子PEA是由各种细胞和组织在不同应激刺激下按需合成的。PEA已被证明具有三个主要作用:镇痛、抑制炎症和通过维持局部稳态来保护细胞。确切的作用机制尚不完全清楚，但有一些假设，包括其在内分泌物局部炎症拮抗(ALIA)通路中的作用，该通路影响肥大细胞脱颗粒。
Finally, probiotics can be defined as supplements with living micro-organisms, that confer one or more health benefits to the host after oral intake. There are many types of probiotics identified by their name based on genus, species and isolate (in that order). Frequently used probiotics in human and veterinary medicine contain bacteria from the genera Lactobacillus or Bifidobacterium. In several studies, the immune-modulating properties of certain probiotics have been demonstrated, including inhibition of T-cell proliferation and increasing serum interleukin (IL)-10 concentrations.
最后，益生菌可以被定义为含有活微生物的补充剂，口服后给宿主带来一种或多种健康益处。根据属、种和分离物(按此顺序)的名称，有许多类型的益生菌。人类和兽药中常用的益生菌含有乳酸菌属或双歧杆菌属的细菌。在一些研究中，某些益生菌的免疫调节特性已被证明，包括抑制T细胞增殖和增加血清白介素(IL)-10浓度。
In veterinary medicine, nutraceuticals are mostly used as dietary supplements or as part of prescription foods. Based on the general effects and mechanisms of action of nutraceuticals, their use in the treatment of IMIDs may confer some benefits. For instance, nutraceuticals may be used to improve clinical signs or to reduce required doses of immunosuppressive drugs as adjunctive therapy, consequently leading to fewer adverse effects. In some IMIDs, nutraceuticals have been used as maintenance therapy after remission of clinical signs was induced by initial therapy with immunomodulatory drugs.However, scientific evidence of its beneficial effect or exact mode of action is often lacking. The aim of this literature review was to present published evidence for the beneficial effects of various nutraceuticals in the treatment of common cDIMIDs and, where possible, to provide conclusions to guide their use in veterinary dermatological practice.
在兽医学中，营养品主要用作膳食补充剂或处方食品的一部分。根据营养品的一般作用和作用机制，将其用于IMIDs的治疗可能会带来一些好处。例如，营养品可用于改善临床症状或作为辅助治疗降低所需的免疫抑制药物剂量，从而使不良反应最小化。在一些IMIDs中，在免疫调节药物的初始治疗诱导临床症状缓解后，营养片已被用作维持治疗。然而，它的有益效果或确切的作用方式往往缺乏科学证据。本文献综述的目的是提出已发表的证据，证明各种营养品在治疗常见cDIMD中的有益作用，并在可能的情况下提供结论，指导其在兽医皮肤病学实践中的使用。
METHODS
方法
Search strategy
搜索策略
Only common cDIMIDs and nutraceuticals were included in this review. The following conditions and nutraceuticals were selected: canine pruritus, allergic dermatitis, canine atopic dermatitis (cAD), cutaneous lupus erythematosus (CLE) variants, pemphigus foliaceus (PF), pemphigus erythematosus (PE), symmetrical lupoid onychodystrophy (SLO), sebaceous adenitis (SA), EFAs (omega-3 and omega-6 FAs), niacinamide, vitamin A and retinoids, PEA, probiotics, vitamin D, vitamin E and zinc.
本综述只包括常见的cDIMD和营养品。选择了以下条件和营养药物:犬瘙痒症、过敏性皮肤病、犬特应性皮肤病(cAD)、皮肤红斑狼疮(CLE)亚型、落叶型天疱疮(PF)、红斑型天疱疮(PE)、对称型狼疮样甲形成不良(SLO)、皮脂腺炎(SA)、EFA(omega-3和omega-6 FAs)、烟酰胺、维生素A和维甲酸、PEA、益生菌、维生素D、维生素E和锌。
A literature search was carried out in the PubMed database covering publications between 1980 and 2020. Different combinations of search terms were used regarding specific disease, disease groups (e.g. autoimmune disease) and specific substances (Table S1). In addition, the Google Scholar database was used and the bibliography of relevant articles was checked for possible related references. Only peer-reviewed original research articles published in English and related to clinical efficacy were included in this review.
在PubMed数据库中进行了文献检索，涵盖1980年至2020年的出版物。针对特定疾病、疾病组(如自体免疫性疾病)和特定物质使用了不同的搜索词组合(表S1)。此外，还使用了谷歌Scholar数据库，并检查了相关文章的参考书目，以寻找可能的相关参考文献。本综述仅纳入同行评审的英文发表的与临床疗效相关的原创研究文章。
Eligible publications were classified into five categories based on study design. Category I provided the highest and V the lowest category of evidence (Table 1). Hereafter, the publications were assessed on additional criteria such as diagnosis (e.g. canine pruritus versus cAD), number of animals included and standardisation of diets. For the final appraisal of the evidence for the use of individual nutraceuticals in a specific disease, evidence was further classified in major, minor or no evidence whereby efficacy was based on clinical outcome measurements.
根据研究设计将符合条件的出版物分为五类。I类提供了最高的证据，V类提供了最低的证据(表1)。此后，对出版物进行了额外的标准评估，如诊断(如犬瘙痒症与cAD)，所包括的动物数量和饮食标准化。为了最终评估在特定疾病中使用个别营养品的证据，进一步将证据分为主要证据、次要证据或无证据，从而根据临床结果测量来确定疗效。
TABLE 1 Categories of evidence.
表1：证据分类
I |
双盲,安慰剂对照,随机研究 |
II |
对照研究 |
III |
无对照研究 |
IV |
回顾性研究 |
V |
病例报告和病例分析 |
Note: Modified from the categories of evidence used by Leung et al.
注:修改自Leung等使用的证据类别。
RESULTS
结果
A total of 64 relevant publications were found. Eligible publications were subdivided based on aetiology into three disease groups: allergic dermatitis, autoimmune and immune-mediated skin disease. Only publications on the selected nutraceuticals per group or disease were described.
共找到64份有关出版物。符合条件的出版物根据病因被细分为三个疾病组:过敏性皮肤病、自体免疫性和免疫介导性皮肤病。仅对每组或每种疾病所选的营养品的出版物进行了描述。
Allergic dermatitis
过敏性皮肤病
Allergic dermatitis in dogs included cAD, adverse food reactions and flea allergy dermatitis, of which cAD currently is the most frequently occurring allergy. It is characterised by a genetically predisposed, chronic inflammatory pruritic dermatitis, often with the presence of elevated environmental allergen-specific immunoglobulin (Ig)E levels. Atopic dogs have an impaired epidermal skin barrier function, with compositional and structural abnormalities, including disorganisation of lipid lamellae, an altered intercellular lipids profile and, in some cases, a filaggrin mutation. Most dogs with allergic dermatitis are treated with immunomodulatory drugs such as glucocorticoids, ciclosporin or oclacitinib. Researched nutraceuticals for dogs with allergic dermatitis were EFAs, probiotics, PEA, niacinamide, vitamins D and E and zinc.
犬的过敏性皮肤病包括cAD、食物副反应和跳蚤过敏性皮肤病，其中cAD是目前最常见的过敏症。它的特征是遗传易感的慢性炎性瘙痒性皮肤病，通常伴有环境过敏原特异性免疫球蛋白(Ig)E水平升高。特应性皮炎患犬表皮皮肤屏障功能受损，成分和结构异常，包括脂质层紊乱，细胞间脂质结构改变，在某些病例中，丝聚合蛋白突变。大多数患有过敏性皮肤病的犬都用免疫调节药物治疗，如糖皮质激素、环孢素或奥拉替尼。研究用于过敏性皮肤病犬的营养品有EFAs、益生菌、PEA、烟酰胺、维生素D和E以及锌。
Essential fatty acids
必需脂肪酸
A total of 25 studies were found on the use of EFAs for the treatment of dogs with allergic dermatitis. Of the 25 studies found, five were classified as Category I, 15 as Category II and five as Category III.
总共有25项关于使用EFA治疗犬过敏性皮肤病的研究。在发现的25项研究中，5项被归类为I类，15项被归类为II类，5项被归类为III类。
A total of six studies looked at canine allergic pruritus, with a combined total of 198 individual dogs that completed the studies. In these studies, the duration of the test period was between two and eightweeks. A total of 19 studies looked at cAD with a combined total of 469 dogs that completed the studies, including controls. The duration of these studies was between eight and 16weeks. Eight of 25 studies used EFA-enriched diets with different compositions. In the remaining studies, various commercial EFA supplements with omega-3 and/or omega-6 FAs in distinct dosages or pure oils (e.g. marine fish oil) were used. In some commercial products, in addition to vitamin E, various minerals and vitamins were present.
共有6项研究观察了犬过敏性瘙痒症，共有198只犬完成了研究。在这些研究中，测试的持续时间在两到八周之间。共有19项研究观察了cAD，总共有469只犬完成了这些研究，包括对照组。这些研究的持续时间在8到16周之间。25项研究中有8项使用了不同成分的富含EFA的饮食。在其余的研究中，使用了不同剂量的含有omega-3和/或omega-6 脂肪酸的各种商业EFA补充剂或纯油(例如海洋鱼油)。在一些商业产品中，除了维生素E，还含有各种矿物质和维生素。
When considering the results of the five Category I studies, a remarkable variation in efficacy was reported. After 60days of supplementation with conjugated LA, black current seed oil or a combination of both, no significant clinical improvement was seen in dogs with cAD. However, treatment with evening primrose oil for nineweeks resulted in significant improvement of erythema in dogs with allergic pruritus. In dogs with cAD, significant improvement in skin and pruritus scores were seen after 10weeks of supplementation with either flax oil or a commercial EFA supplement with EPA and DHA.In two Category I studies, a drug-sparing effect in dogs with cAD and food-induced AD was shown after 12weeks of EFA supplementation. A significant reduction in pruritus was seen, and the used oral prednisolone or ciclosporin dose was significantly lower than that of the placebo. Used EFA dosages in these Category I studies are shown in Table 2a. In addition to these findings, in the lower-category studies on EFAs similar beneficial effects were seen.
当考虑到五个I类研究的结果时，报告了显著的疗效差异。在补充结合LA、黑流菜籽油或两者联用60天后，在cAD患犬上没有看到明显的临床改善。然而，用月见草油治疗九周后，过敏性瘙痒症犬的皮肤发红有了显著改善。在cAD患犬中，在补充亚麻油或含有EPA和DHA的商业EFA补充剂10周后，可以看到皮肤和瘙痒评分的显著改善。在两项I类研究中，在补充EFA 12周后，cAD和食物诱导性AD患犬显示出药物节省效应。瘙痒症状明显减轻，口服泼尼松龙或环孢素剂量明显低于安慰剂。在这些第一类研究中使用的EFA剂量见表2a。除了这些发现外，在低类别的EFAs研究中也看到了类似的有益影响。
Probiotics
益生菌
Four studies (three Category I and one Category II) were found on the use of probiotics for treatment of cAD. A combined total of 77 dogs were treated with different types of probiotics for a duration of eight to 12 weeks compared with 59 control dogs treated with placebo (n=38) or antihistamine (n=21). The genera used in the different studies were Lactobacillus (n=2) and Enterococcus (n=2), although the used species differed between studies. In 28 dogs, treatment with L. sakei probio65 for eight weeks resulted in significant reduction in Canine Atopic Dermatitis Extent and Severity Index (CADESI) scores, but not pruritus Visual Analog Scale (pVAS) scores, compared with the placebo group. In a study by Osumi et al., treatment with a heatkilled Enterococcus faecalis FK-23 isolate resulted in significant decrease in CADESI scores after 12 weeks of supplementation compared with the placebo group. No significant adjunctive effect of the probiotic on reduction in the medication score of concurrent drugs was found. Twelve weeks of supplementation with a commercial product containing E. faecium SF68 (1×108 cfu/g twice daily) had no significant effect on the required oclacitinib dose in 11 dogs compared with the placebo dose (n=10). By contrast, reduction in required medication was reported after 12 weeks of treatment with Lactobacillus paracasei K71 in 20 dogs with mild-to-moderate AD compared with antihistamine-treated dogs (n=21).
4项研究(3项I类研究和1项II类研究)发现使用益生菌治疗cAD。总共有77只犬在8至12周的时间内接受了不同类型的益生菌治疗，而59只对照组犬接受了安慰剂(n=38)或抗组胺(n=21)治疗。不同研究中使用的属为乳酸菌(n=2)和肠球菌(n=2)，但不同研究中使用的物种不同。在28只犬中，与安慰剂组相比，使用L. sakaki probio65治疗8周后，犬特应性皮炎严重程度指数(CADESI)评分显著降低，但瘙痒视觉模拟量表(pVAS)评分没有显著降低。在Osumi等人的一项研究中，与安慰剂组相比，使用热杀粪肠球菌fb -23分离物治疗12周后，CADESI评分显著降低。益生菌对同期用药评分的降低无明显的辅助作用。与安慰剂剂量相比，11只犬在12周内补充含有屎肠杆菌SF68的商业产品(1×108 cfu/g，每天两次)对所需的奥拉替尼剂量没有显著影响(n=10)。相比之下，与抗组胺治疗的犬相比，20只轻度至中度AD的犬在使用副干酪乳杆菌K71治疗12周后，所需的药物减少(n=21)。
Palmitoylethanolamide
十六酰胺乙醇
One study (Category III) was found on the use of PEA in cAD. A total of 160 dogs were treated with ultramicronised PEA for eightweeks. Treatment resulted in a significant reduction in pVAS and skin lesion scores within eightweeks in >50% of the PEA-treated dogs. In addition, mean total quality of life (QoL) score was significantly reduced, with 45% of the dogs having a QoL score described for healthy dogs.
发现一项关于PEA在cAD中的使用的研究(III类)。共有160只犬接受了8周的超微PEA治疗。经PEA治疗的犬在8周内pVAS和皮肤病变评分显著降低，达到>50%。此外，平均总生活质量(QoL)评分显著降低，45%的犬的QoL评分为健康犬。
Vitamins and minerals
维生素和矿物质
One study (Category III) was found on the use of niacinamide in cAD. In that study, 19 dogs were treated with niacinamide and tetracycline for twoweeks. The most frequently used dosage of this drug combination, namely 250mg of each drug for dogs 10kg three times daily, is referred to in this review unless stated otherwise. Most dogs in this study (15 of 19) showed poor response based on owners' observation of pruritus reduction. The pruritus was successfully controlled in only one dog.
一项研究(III类)发现了烟酰胺在cAD中的使用。在这项研究中，19只犬接受了烟酰胺和四环素两周的治疗。除非另有说明，本综述中提到了该药物组合最常用的剂量，即每种药物250mg，每天三次，适用于10kg的犬。这项研究中的大多数犬(19只中的15只)根据主人对瘙痒减少的观察表现出效果不佳。只有一只犬的瘙痒被成功控制。
One study (Category I) was found on the use of vitamin D (cholecalciferol) in cAD. In that study, 16 atopic dogs were treated with vitamin D for eight weeks. Significant improvement in pruritus and CADESI scores was seen compared with the placebo group.
一项研究(I类)发现维生素D(胆钙化醇)在cAD中的使用。在这项研究中，16只特应性皮炎犬接受了8周的维生素D治疗。与安慰剂组相比，瘙痒和CADESI评分有显著改善。
Likewise, one Category I study was found on the use of vitamin E in cAD. A total of 14 dogs were treated with vitamin E for eightweeks. All dogs were fed the same home-made diet and were treated with an antihistaminic drug. Supplementation of vitamin E significantly improved CADESI scores compared with the placebo group (n = 15). However, pruritus scores did not differ significantly.
同样，也发现一项关于维生素E在CAD中的使用的I类研究。共有14只犬接受了为期8周的维生素E治疗。所有的犬都喂食同样的自制食物，并服用抗组胺药物。与安慰剂组相比，补充维生素E显著改善CADESI评分(n = 15)。然而，瘙痒评分没有显著差异。
Finally, one study (Category II) was found on the use of zinc in atopic dogs concomitantly treated with glucocorticoids or ciclosporin. In that cross-over study, 27 dogs were treated with zinc methionine in combination with biotin and EFAs (0.1mg/kg biotin, 7.1mg/ kg EPA and 4.7mg/kg DHA once daily), compared with a control product containing only EFAs and biotin. Supplementation of zinc methionine resulted in a significant reduction in pruritus scores in dogs treated with glucocorticoids and in skin lesion scores in dogs treated with glucocorticoids or ciclosporin.
最后，一项研究(II类)发现了在糖皮质激素或环孢素治疗的特应性皮炎犬中使用锌。在这项交叉研究中，27只犬接受了蛋氨酸锌与生物素和EFAs的联合治疗(0.1mg/kg生物素，7.1mg/ kg EPA和4.7mg/kg DHA，每天一次)，与仅含有EFAs和生物素的对照产品进行比较。补充蛋氨酸锌可显著降低糖皮质激素治疗犬的瘙痒评分，降低糖皮质激素或环孢素治疗犬的皮肤病变评分。
Autoimmune skin disease
自体免疫性皮肤病
The most commonly occurring autoimmune skin diseases are variants of the pemphigus complex and CLE. These diseases are characterised by the activation of autoantibodies against specific structures of the epidermis, leading to severe skin lesions. For the management of lesions, the use of immunomodulatory drugs often is indispensable. The most frequently occurring pemphigus variants are PF and PE, which also are referred to as superficial pemphigus. For CLE, different variants have been described in the literature: discoid lupus erythematosus (DLE), exfoliative CLE (ECLE), mucocutaneous lupus erythematosus (MCLE) and vesicular CLE (VCLE). Of DLE, a localised (facial) and generalised form (GDLE) have been described.
最常见的自体免疫性皮肤病是天疱疮复合物和CLE的亚型。这些疾病的特点是针对表皮特定结构的自体抗体的激活，导致严重的皮肤病变。对于病变的管理，使用免疫调节药物往往是必不可少的。最常见的天疱疮亚型是PF和PE，也被称为浅表性天疱疮。对于CLE，文献中描述了不同的亚型:盘状红斑狼疮(DLE)、表皮剥脱性CLE (ECLE)、皮肤粘膜红斑狼疮(MCLE)和水疱型CLE (VCLE)。对于DLE，已经描述了局部(面部)和全身型(GDLE)。
Superficial pemphigus
浅表性天疱疮
Researched nutraceuticals for dogs with superficial pemphigus were EFAs and niacinamide.
研究的用于犬浅表性天疱疮的营养品为EFAs和烟酰胺。
Essential fatty acids
必需脂肪酸
One study (Category IV) was found reporting the use of EFAs in three dogs with PF as initial or maintenance therapy. In this study, two dogs were controlled with EFA supplementation, although no information on dosage, duration and type or source of EFAs was recorded.
一项研究(IV类)报告了在三只PF患犬中使用EFAs作为初始或维持治疗。在这项研究中，虽然没有记录EFAs的剂量、持续时间和类型或来源的信息，但两只犬补充了EFA。
Niacinamide
烟酰胺
Five studies (two Category III and three Category IV) were found reporting the use of niacinamide in dogs with superficial pemphigus. A combined total of 48 dogs were treated and were diagnosed having PF (n = 10), PE (n = 4) and superficial pemphigus (n = 34). Most dogs were treated with niacinamide and tetracycline in the aforementioned dosage, while in some dogs, doxycycline was used. Duration of treatment varied from 22 days to 2071 days. In the study by Gomez et al., no clinical outcome was recorded and in two other studies various results were seen. In the Category III study by White et al. only two of 10 dogs showed a good response, defined as 50–90% resolution of clinical signs within eight weeks of treatment. In the Category IV study by Edginton et al., 18 of 29 dogs (62%) showed a beneficial response to treatment with niacinamide and tetracycline within 3–6 weeks with an optimum at 12–20 weeks.
五项研究(两项III类研究和三项IV类研究)报告了在浅表性天疱疮患犬上使用烟酰胺。共有48只犬接受治疗，诊断为PF (n=10)、PE (n=4)和浅表性天疱疮(n=34)。大多数犬使用上述剂量的烟酰胺和四环素治疗，而在一些犬中，使用多西环素。治疗时间从22天到2071天不等。在Gomez等人的研究中，没有记录临床结果，在另外两项研究中看到了各种结果。在White等人的III类研究中，10只犬中只有两只表现出良好效果，定义为在治疗后8周内临床症状缓解50-90%。在Edginton等人的IV类研究中，29只犬中有18只(62%)在3-6周内对烟酰胺和四环素治疗表现出有效，最佳时间为12-20周。
Cutaneous lupus erythematosus
皮肤红斑狼疮
Researched nutraceuticals for dogs with CLE variants were EFAs, niacinamide, vitamin A, retinoids, vitamin E and zinc.
为CLE亚型患犬研究的营养品有EFAs、烟酰胺、维生素A、维甲酸、维生素E和锌。
Essential fatty acids
必需脂肪酸
Four studies (two Category IV and two Category V) were found reporting the use of EFAs in CLE. A combined total of 19 dogs were treated with EFAs, 17 dogs with ECLE and two dogs with (generalised) DLE. Unfortunately, information on type of EFAs used, or dosage, duration and specific outcome was scarcely given. In nine dogs, mild-to-moderate improvement was seen, with most dogs receiving concurrent medications. In the study by Vroom et al., three of four German shorthaired pointers with ECLE showed improvement when treated with different commercial EFA supplements, providing EPA, DHA and GLA in various dosages with or without added vitamins and minerals. One of these dogs received concurrent niacinamide and tetracycline.
四项研究(两项IV类研究和两项V类研究)报告了EFAs在CLE中的使用。共有19只犬接受了EFAs治疗，17只犬接受了ECLE治疗，2只犬接受了(全身型)DLE治疗。不幸的是，关于所使用的EFAs类型、剂量、持续时间和具体结果的信息几乎没有给出。在9只犬中，可以看到轻度到中度的改善，大多数犬同时接受药物治疗。在Vroom等人的研究中，4只具有ECLE的德国短毛犬中有3只在使用不同的商业EFA补充剂(提供不同剂量的EPA、DHA和GLA，添加或不添加维生素和矿物质)时表现出改善。其中一只犬同时服用烟酰胺和四环素。
Niacinamide
烟酰胺
Fourteen studies (one Category III, five Category IV and eight Category V) were found reporting the use of niacinamide as therapy for CLE variants. A combined total of 69 dogs (DLE n = 41, MCLE n = 14, ECLE n = 8, VCLE n = 3, GDLE n = 3) were treated with niacinamide and cyclic antibiotics. For the dogs of which the duration of treatment was reported, most were treated for a minimum of sixweeks.
14项研究(1项III类，5项IV类和8项V类)报告了使用烟酰胺治疗CLE亚型。共69只犬(DLE 41只、MCLE 14只、ECLE 8只、VCLE 3只、GDLE 3只)接受烟酰胺和全身性抗生素治疗。对于报告了治疗持续时间的犬，大多数接受了至少六周的治疗。
When considering DLE or GDLE, 25 of 34 dogs were successfully treated with niacinamide and cyclic antibiotics without concurrent medications. Improvement of clinical signs was seen mostly within one to three months (range oneweek to sixmonths). However, in the remaining dogs poor-to-no response was seen or long-term treatment was not effective.
在考虑DLE或GDLE时，34只犬中有25只成功地使用烟酰胺和全身性抗生素治疗，没有同时使用药物。临床症状的改善大多发生在1 - 3个月内(范围1 - 6个月)。然而，在其余的犬中，没有反应或长期治疗无效。
When considering MCLE, four dogs were satisfactorily controlled or showed complete remission with niacinamide and tetracycline therapy which eventually could be reduced to once daily in three of them. For 10 dogs from two Category V studies, the individual outcome was not available.
在考虑MCLE时，四只犬在烟酰胺和四环素治疗下得到了令人满意的控制或完全缓解，其中三只犬最终可以减少到每天一次。来自两项V类研究的10只犬的个体结果不可用。
When considering VCLE, three dogs were treated with niacinamide and tetracycline. Poor-to-no response was seen in two dogs of which one also was treated with concurrent medications. One dog was successfully treated after initial therapy with topical 0.1% tacrolimus for 14days.
在考虑VCLE时，对三只犬进行了烟酰胺和四环素治疗。两只犬的反应很差，甚至没有反应，其中一只也同时接受了药物治疗。一只犬在最初的0.1%他克莫司外用治疗14天后成功治疗。
When considering ECLE, eight dogs were treated with niacinamide and tetracycline, or in some cases doxycycline. In one Category IV study, three of five German shorthaired pointers showed some improvement. However, concurrent topical and systemic treatments were given and all dogs were eventually euthanised. Treatment with niacinamide and tetracycline resulted in no improvement in three dogs and≥75% improvement in two dogs of which one received concurrent EFAs.
在考虑ECLE时，8只犬接受了烟酰胺和四环素治疗，在某些情况下还使用了多西环素。在一项第四类研究中，五只德国短毛犬中有三只表现出了一些进步。然而，同时给予外部和全身治疗，所有的犬最终都被安乐死。烟酰胺和四环素治疗3只犬没有改善，其中2只犬改善≥75%，其中1只同时接受EFAs治疗。
Other vitamins and minerals
其他维生素和矿物质
Five studies (four Category IV and one Category V) were found reporting the use of vitamin A, retinoids, vitamin E and/or zinc for treatment in CLE variants. In one dog with DLE, vitamin E was used as adjunctive therapy with good response. In contrast, in one dog with VCLE, adjunctive therapy with vitamin E (400IU twice daily) resulted in poor response. Therapy with subsequent use of vitamin A (20,000IU/ day), E (300mg/day) and etretinate (25mg/day) in a German shorthaired pointer with ECLE was not effective. One German shorthaired pointer showed temporal remission with retinoids and topical therapy. However, no further information on treatment was given and the dog was eventually euthanised. Specific information on the use and efficacy of vitamin A, vitamin E or zinc in ECLE and DLE was not reported.
5项研究(4项IV类研究和1项V类研究)报告了使用维生素A、维甲酸、维生素E和/或锌治疗CLE亚型。在一只患有DLE的犬中，使用维生素E作为辅助治疗，效果良好。相比之下，在一只患有VCLE的犬中，维生素E(每天两次400IU)的辅助治疗导致效果不佳。在患有ECLE的德国短毛指示犬中，随后使用维生素A (20000IU/天)、E (300mg/天)和依曲替酯(25mg/天)的治疗无效。一只德国短毛指示犬在维甲酸和外部治疗后出现短暂缓解。然而，没有进一步的治疗信息，这只犬最终被安乐死。关于维生素A、维生素E或锌在ECLE和DLE中的使用和疗效的具体信息尚未报道。
Immune-mediated skin disease
免疫介导性疾病
Relatively common immune-mediated skin diseases are SLO and SA. The exact aetiology of both conditions is unknown, yet an immune-mediated inflammatory response results in the development of clinical symptoms. Management often is multimodal, combining topical and systemic therapies.
相对常见的免疫介导性皮肤病为SLO和SA。这两种疾病的确切病因尚不清楚，但免疫介导的炎症反应导致临床症状的发展。治疗通常是多模式的，结合外部治疗和全身治疗。
Symmetrical lupoid onychodystrophy
对称性狼疮样甲形成不良
Researched nutraceuticals for dogs with SLO were EFAs, niacinamide, vitamin B complex, biotin and zinc.
研究的SLO犬的营养品有EFAs、烟酰胺、维生素B复合物、生物素和锌。
Essential fatty acids
必需脂肪酸
Six studies (one Category II, three Category IV and two Category V) were found reporting the use of EFAs in SLO. A combined total of 67 dogs were treated. In the Category II study, the duration of treatment of seven Gordon setters was sixmonths.In that study, a commercial EFA supplement with EPA, DHA and vitamin E was compared with ciclosporin treatment while all dogs were fed an omega-3 FA-enriched diet. Both groups in this study showed significant clinical improvement, measured by numbers of healthy normal nails with no significant difference between groups. In one Category V study, the duration of treatment was 30–52months for five dogs. All showed a good response to EFA supplementation within 11– 15weeks. Two of five dogs were treated initially with concurrent prednisolone. In the remaining studies, 55 dogs were treated with commercial EFA supplements with various amounts of omega-3 and omega-6 FAs, often with additional vitamin E. Duration of treatment was not known for all dogs, and most dogs were treated for ≥12weeks. Of 55 dogs, 33 showed clinical improvement with EFA supplementation, resulting in cessation of onycholysis, onychomadesis and onychalgia. Six of these dogs were treated with concurrent medications.
六项研究(一项II类，三项IV类和两项V类)报告了在SLO中使用EFAs。总共有67只犬接受了治疗。在II类研究中，7例戈登雪达犬的治疗持续时间为6个月。在这项研究中，将含有EPA、DHA和维生素E的商业EFA补充剂与环孢素治疗进行了比较，同时所有的犬都喂食富含omega-3脂肪酸的饮食。本研究中两组均表现出显著的临床改善，以健康正常指甲的数量来衡量，两组间无显著差异。在一项V类研究中，5只犬的治疗持续时间为30 - 52个月。所有患去哪在11 - 15周内对补充脂肪酸均表现出良好的反应。5只犬中有2只最初同时使用泼尼松龙治疗。在其余的研究中，55只犬接受了含有不同数量的omega-3和omega-6脂肪酸的商业EFA补充剂的治疗，通常还含有额外的维生素E。所有犬治疗的持续时间并不是都知道，大多数犬的治疗时间≥12周。55只犬中，33只在补充EFA后表现出临床改善，导致甲脱落、脱甲症和甲疼痛停止。其中6只犬同时接受了药物治疗。
Niacinamide
烟酰胺
Three studies (two Category IV and one Category V) were found reporting the use of niacinamide in SLO. A combined total of 35 dogs were treated with niacinamide and cyclic antibiotics for a minimum of sevenweeks, with or without concurrent therapies (e.g. prednisolone and EFAs). In the study by Ziener et al., niacinamide and tetracycline were used in nine dogs as short-term initial therapy of 50–90days. In some dogs, niacinamide initially was given twice daily. In 12 of 35 dogs, partial-to-excellent clinical improvement was seen, with most dogs having (nonpainful) onychodystrophy. Another three dogs showed improvement with niacinamide, EFAs and oral prednisolone therapy. In some dogs, administration of niacinamide and tetracycline could be reduced to once or twice daily.
三项研究(两项IV类研究和一项V类研究)报告了烟酰胺在SLO中的使用。总共有35只犬接受了至少7周的烟酰胺和全身性抗生素治疗，同时或不同时进行治疗(例如泼尼松龙和EFAs)。在Ziener等人的研究中，9只犬使用烟酰胺和四环素作为50 - 90天的短期初始治疗。在一些犬中，最初每天两次服用烟酰胺。35只犬中有12只出现了部分到良好的临床改善，大多数犬有(无疼痛)甲营养不良。另外3只犬在烟酰胺、EFAs和口服泼尼松龙治疗后表现出改善。在一些犬，烟酰胺和四环素的管理可以减少到每天一次或两次。
Other vitamins and minerals
其他微生物和矿物质
Two studies (one Category IV and one Category V) were found reporting the use of B vitamins and zinc for treatment of SLO. In two dogs, biotin and zinc resulted in no improvement. In one dog, treatment with topical ketoconazole (twice per week), vitamin B complex (B1 30mg, B2 30mg, B6 10mg daily) and zinc (2mg/kg once daily) resulted in no clinical response after fivemonths of therapy.
两项研究(一项IV类研究和一项V类研究)报告了使用B族维生素和锌治疗SLO。在两只犬中，生物素和锌没有改善。在一只犬中，使用外用酮康唑(每周两次)、维生素B复合物(B1 30mg, B2 30mg, B6 10mg每天)和锌(2mg/kg每天一次)治疗5个月后没有临床效果。
Sebaceous adenitis
皮脂腺炎
Researched nutraceuticals for dogs with SA were EFAs, vitamin A, retinoids and zinc.
为SA患犬研究的营养品有脂肪酸、维生素A、维甲酸和锌。
Essential fatty acids
必需脂肪酸
Three Category IV studies were found reporting the use of EFAs as adjunctive therapy in SA. A combined total of 68 dogs were treated with EFAs, although often no information on dosage, duration or type of EFAs was recorded, and specific information on individual treatment protocol and outcome was lacking. In these studies, significant improvement of clinical signs was seen. However, almost all of these dogs were treated with concurrent therapies, including ciclosporin, vitamin A, glucocorticoids and/or topical therapy.
有三项IV类研究报告了EFAs作为SA的辅助治疗。共有68只犬接受了EFAs治疗，但通常没有记录有关EFAs剂量、持续时间或类型的信息，而且缺乏关于个别治疗方案和结果的具体信息。在这些研究中，临床症状有显著改善。然而，几乎所有这些犬都接受了同时治疗，包括环孢素、维生素A、糖皮质激素和/或外部治疗。
Vitamin A
维生素A
The same Category IV studies as for EFAs were found reporting the use of vitamin A as adjunctive therapy. In the study by Lam et al., 12 of 21 dogs showed improvement of clinical signs after at least onemonth of vitamin A therapy (mean dose of 1094IU/kg/day). Vitamin A was the sole treatment in two dogs, of which one showed 50% improvement. In the study by Frazer et al., seven of 12 Havanese dogs were treated with vitamin A (704–1126IU/kg/day) of which four showed mild-to-marked clinical improvement and three were lost in follow-up. In the study by Hernblad Tevell et al., vitamin A was recommended in 16% of 51 dogs as additional treatment. In this study, although significant improvement of seborrhoea and degree of severity was seen, individual outcome data were not available.
与EFAs相同的IV类研究报告了维生素A作为辅助治疗的使用。在Lam等人的研究中，21只犬中有12只在至少一个月的维生素A治疗后(平均剂量为1094IU/kg/天)表现出临床症状的改善。在两只犬上，维生素A是唯一的治疗方法，其中一只改善了50%。在弗雷泽等人的研究中，12只哈威那犬中有7只服用了维生素A (704-1126IU /kg/天)，其中4只表现出轻微到明显的临床改善，3只在随访中消失。在Hernblad Tevell等人的研究中，推荐给51只犬中16%的犬服用维生素A作为额外治疗。在本研究中，虽然脂溢血和严重程度得到了显著改善，但没有获得个体结果数据。
Retinoids
维甲酸
One Category III study on the use of retinoids for treatment of SA was found. A total of 20 of 36 dogs were successfully treated with either isotretinoin or etretinate for a minimum of twomonths. Treatment resulted in >50% improvement in clinical signs such as alopecia and severity of scaling. Most dogs showed improvement within sixweeks. In a few dogs that did not respond to the first retinoid prescribed, treatment with the other retinoid resulted in clinical improvement (n = 3), and three of four dogs benefitted clinically from a doubled dose.
一项关于使用维甲酸治疗SA的III类研究被发现。36只犬中有20只成功地接受了异维甲酸或依曲替酯至少两个月的治疗。治疗后，临床症状如脱毛和皮屑严重程度改善50%。大多数犬在六周内表现出改善。在少数对第一种维甲酸药物没有效的犬中，使用另一种维甲酸药物治疗可导致临床改善(n = 3)， 4只犬中有3只从双倍剂量的治疗中获益。
Zinc
锌
There was one study found reporting on the use of zinc supplementation in dogs with SA. Three dogs were unsuccessfully treated with zinc before enrolment in a study on efficacy of retinoids. Information on dose and duration was not recorded.
有一项研究报告了在SA患犬中使用锌补充剂。在一项关于维甲酸功效的研究中，有三只犬在接受锌治疗前没有成功。没有记录剂量和持续时间的信息。
DISCUSSION
讨论
In the past 40years, considerable research has been published on the use of various nutraceuticals in the management of cDIMIDs. Many of the described nutraceuticals in this review have been used in general or referral practice. However, major supportive evidence from large randomised, placebo-controlled, doubleblinded clinical trials could not be found.
在过去的40年里，已经发表了大量关于使用各种营养品治疗cDIMIDs的研究。在这篇综述中描述的许多营养品已在全科或转诊医院中使用。然而，从大型随机、安慰剂对照、双盲临床试验中无法找到主要的支持性证据。
Allergic dermatitis
过敏性皮肤病
Based on the results on allergic dermatitis, minor evidence was found for the beneficial use of omega-3 and/ or omega-6 FAs such as EPA and DHA alone, evening primrose oil (providing mostly LA and GLA) or flax oil (providing mostly ALA and LA). In addition, minor evidence was found for a prednisolone or ciclosporin drug-sparing effect of the combination of omega-3 and omega-6 FAs.
基于过敏性皮肤病的结果，很少有证据表明omega-3和/或omega-6脂肪酸的优势，如单一EPA和DHA，月见草油(主要提供LA和GLA)或亚麻油(主要提供ALA和LA)。此外，还发现少量证据表明omega-3和omega-6脂肪酸联合使用会产生泼尼松龙或环孢素药物节省效应。
Traditionally, EFAs have been referred to as one group. However, as each individual FA has its own metabolic functions, efficacy may depend on type of FA, dosage and ratio versus other FAs. Therefore, we believe that a distinction needs to be made between the type of FA when discussing efficacy of particular EFAs. In addition, when pure oils, commercial supplements or diets are used, other substances, besides the active ingredients, may be administered that also may have certain effects in the body. For instance, commercial EFA supplements often contain additional vitamin E, which may have additional positive effects on its own. There is a close relationship between dietary intake of polyunsaturated EFAs and vitamin E requirement. Therefore, co-supplementation of polyunsaturated EFAs with vitamin E is strongly advised.
传统上，EFA被称为一个整体。然而，由于每个FA都有自己的代谢功能，功效可能取决于FA的类型、剂量和与其他FA的比例。因此，我们认为，在讨论特定EFAs的功效时，需要对不同类型的FA进行区分。此外，当使用纯油、商业补品或饮食时，除了活性成分外，还可能使用其他物质，这些物质也可能对身体产生一定的影响。例如，商业EFA补充剂通常含有额外的维生素E，这本身可能有额外的积极作用。膳食中多不饱和脂肪酸的摄入与维生素E需求量密切相关。因此，强烈建议将多不饱和脂肪酸与维生素E联合补充。
In general, EFAs have been the most researched nutraceutical in cAD as a result of their potential beneficial effects on the immune response, skin inflammation and epidermal barrier function. Compared with healthy dogs, atopic dogs have a significant decrease in lipid content of the stratum corneum, which can be normalised after oral supplementation of omega-3 and omega-6 FAs in a 1:5 ratio (LA, GLA, EPA, DHA and vitamin E).Omega-3 and omega-6 FAs may alter plasma FA composition to a certain degree, in which total dietary intake, dose and/or ratio of FAs appear to play a role. Changes in the FA composition in serum and skin can be detected after three to 12weeks of supplementing the diet with olive or sunflower oil. Hence, establishment of clinical efficacy would be expected after at least threeweeks of supplementation. However, significant clinical improvement was not seen in most studies until eight to 12weeks.
总的来说，由于EFAs对免疫反应、皮肤炎症和表皮屏障功能的潜在优势，已成为cAD中研究最多的营养品。与健康犬相比，特应性皮炎犬角质层脂质含量明显降低，口服omega-3和omega-6脂肪酸 1:5比例后可恢复正常(LA、GLA、EPA、DHA和维生素E)。omega-3和omega-6脂肪酸可在一定程度上改变血浆脂肪酸组成，其中总膳食摄入量、剂量和/或比例似乎起作用。在用橄榄油或葵花籽油补充饮食3至12周后，可以检测到血清和皮肤中FA成分的变化。因此，临床疗效的确立将在补充至少三周后。然而，在大多数研究中，直到8至12周才发现明显的临床改善。
Overall efficacy of EFA supplementation is difficult to assess and compare. Most of the published studies showed one or more limitations, amongst others variability in diagnoses, subjective outcome measurements, lack of standardisation of the diet (before and during the study) and lack of a placebo-control group. Moreover, documentation of the total and individual EFA intake (diet and supplementation) and dosages of the specific types of FA often are lacking, even in some Category I studies. Preferably, calculated EFA dosage should be based on metabolic body weight. In addition, maintenance dog food may have changed over the years; different concentrations, changes in composition and ratios of EFAs may have had an effect on clinical outcome. Other factors which may influence clinical outcome are interactions between nutrients, disease progression, severity of inflammation and the state of health of the animal. For example, in dogs with chronic AD, EFA supplementation was found to be less effective compared with dogs with early-stage AD.
EFA补充剂的总体疗效难以评估和比较。大多数已发表的研究显示出一个或多个局限性，其中包括诊断的可变性、主观结果测量、饮食(研究前和研究期间)缺乏标准化以及缺乏安慰剂对照组。此外，即使在一些第一类研究中，也经常缺乏关于总摄入量和个人脂肪酸摄入量(饮食和补充)以及特定类型脂肪酸剂量的记录。最好是根据代谢体重计算EFA剂量。此外，多年来，犬粮可能已经发生了变化;EFAs的不同浓度、组成和比例的变化可能对临床结果有影响。其他可能影响临床结果的因素是营养、疾病进展、炎症严重程度和动物健康状况之间的相互作用。例如，在慢性AD患犬中，与早期AD患犬相比，补充EFA的效果较差。
As a consequence of the heterogeneity of the studies, the wide range of products and the lack of feed standardisation, no definitive statement can be made about which type of EFAs, combinations or dosages should be used for optimal results. However, Bauer et al. recommended the use of 125mg EPA and DHA per kg metabolic body weight for inflammatory diseases including cAD based on three studies. Based on findings in human literature, the combination of GLA and omega-3 FAs (EPA and DHA) are expected to have the highest anti-inflammatory potential.
由于研究的异质性、产品的广泛范围和缺乏饲料标准化，无法确定应使用哪种类型的EFAs、组合或剂量以获得最佳结果。然而，Bauer等人根据三项研究建议，对于包括cAD在内的炎性疾病，每公斤代谢体重使用125mg EPA和DHA。根据人类文献的发现，GLA和omega-3脂肪酸(EPA和DHA)的组合被认为具有最高的抗炎潜力。
For the use of probiotics in cAD, minor evidence was found for the beneficial use of specific Lactobacillus and Enterococcus species. Also, minor evidence was found for a drug-sparing effect of L. paracasei K71. By contrast, no evidence was found for a drug-sparing effect of E. faecalis FK-23 and E. faecium SF68, the latter being used with oclacitinib. In a similar way to EFAs, when using probiotics, a distinction should be made between specific species and isolates used, as each type may exert different effects. Interestingly, clinical efficacy of the commonly used L. rhamnosus GG isolate in humans, to the best of the knowledge of the authors, has not been studied in dogs with AD. However, a preventive role of L. rhamnosus GG, when administered perinatally, has been suggested for both human and canine AD. Alterations of the skin and gut microbiome resulting in dysbiosis were demonstrated in various disease processes, including AD. In addition to skin barrier defects, impairment of the intestinal barrier also may play a role in development of AD. In both dogs and humans, some Lactobacillus species have shown to improve intestinal barrier function. The role of the skin and gut microbiome in the pathophysiology of cAD is not yet elucidated.
对于在cAD中使用益生菌，很少有证据表明使用特定的乳酸菌和肠球菌是有益的。此外，还发现少量证据表明副干酪乳杆菌K71具有药物节省作用。相比之下，没有证据表明粪肠杆菌FK-23和粪肠杆菌SF68具有药物节省作用，后者与奥拉替尼联合使用。与EFAs类似，在使用益生菌时，应区分所使用的特定菌种和分离菌，因为每种类型可能产生不同的效果。有趣的是，据作者所知，常用的鼠李糖乳杆菌GG分离物在人类中的临床疗效尚未在AD患犬上进行研究。然而，L.鼠李糖GG的预防作用，当时，已建议人类和犬的AD围产期给药。皮肤和肠道微生物组的改变导致生态失调被证明在各种疾病过程中，包括AD。除了皮肤屏障缺陷外，肠屏障的损害也可能在AD的发展中发挥作用。在犬和人上，一些乳酸菌已经被证明可以改善肠道屏障功能。皮肤和肠道微生物组在cAD病理生理学中的作用尚未阐明。
Only limited research on the use of PEA and individual vitamins and minerals in the treatment of cAD was reported. Information on oral bioavailability of these nutraceuticals often is limited, which also can depend on the chemical form of certain nutrients. Minor evidence was found for the beneficial use of ultramicronised PEA in cAD. In human medicine, there is some debate on the effectiveness of different forms of PEA. In a rat model of inflammatory pain, orally administered micronised and ultramicronised PEA resulted in significant improvement on inflammation and analgesia compared with nonmicronised PEA. It might, therefore, be relevant to take the chemical form of PEA into account when using PEA. However, comparative studies on this topic are lacking in both humans and dogs.
关于使用PEA和单一维生素和矿物质治疗cAD的研究报道有限。关于这些营养品的口服生物利用度的信息通常是有限的，这也取决于某些营养素的化学形式。很少有证据表明超微PEA在CAD中是有益的。在人类医学中，对不同形式的PEA的有效性存在一些争论。在炎性疼痛大鼠模型中，与未微粉化的PEA相比，口服微粉化和超微粉化的PEA可显著改善炎症和镇痛。因此，在使用PEA时，考虑到PEA的化学形式可能是相关的。然而，关于这一主题的比较研究在人类和犬都缺乏。
Minor evidence was found for the use of vitamin D as adjunctive therapy in cAD. Several studies showed that humans with AD have lower serum levels of vitamin D compared with healthy individuals. In the eight-week clinical trial of Klinger et al., improvement of pruritus correlated with an increased level of the vitamin D metabolite calcidiol in the serum. No adverse effects were seen, although the used cholecalciferol dosage of 300– 1400IU/kg/day far exceeded the safe upper limit for vitamin D that was proposed by the National Research Council or FEDIAF. In another study, no significant difference in serum calcidiol was seen in dogs with AD compared with healthy controls. Interestingly, serum calcidiol levels were higher in atopic dogs that showed a good response to oral prednisolone treatment compared with atopic dogs with less favourable response to therapy. More information is needed on the longterm effects of supplementation with cholecalciferol and the possible risk for vitamin D toxicity. It is thus recommended to consult nutritional guidelines and check the amounts present in the diet to prevent possible overdose.
很少有证据表明使用维生素D作为cAD的辅助治疗。几项研究表明，与健康个体相比，AD患者血清中维生素D的水平较低。在Klinger等人为期八周的临床试验中，瘙痒的改善与血清中维生素D代谢物钙二醇水平的升高有关。虽然使用的300 - 1400IU/kg/天的胆钙化醇剂量远远超过了国家研究委员会或FEDIAF提出的维生素D的安全上限，但没有发现不良反应。在另一项研究中，与健康对照组相比，AD患者的血清钙二醇没有明显差异。有趣的是，与对治疗效果不佳的特应性皮炎犬相比，口服泼尼松龙治疗反应良好的特应性皮炎犬血清钙二醇水平较高。补充胆钙化醇的长期影响和维生素D中毒的可能风险需要更多的信息。因此，建议咨询营养指南，并检查饮食中存在的量，以防止可能的过量。
For the beneficial use of vitamin E or zinc methionine as adjunctive therapy in cAD, minor evidence was found. As with vitamin D, there are studies showing that serum zinc levels may be reduced in humans with AD.In comparison, in atopic dogs lower plasma vitamin E concentrations were found compared with healthy individuals. Treatment with vitamin E resulted in significant higher plasma levels of vitamin E and total antioxidant capacity in atopic dogs. These findings may indicate an altered vitamin or mineral balance in AD. However, little is known about the relationship between these nutrients and AD in both humans and dogs.
对于维生素E或蛋氨酸锌作为cAD辅助治疗的优势，发现的证据很少。与维生素D一样，有研究表明，AD患者的血清锌水平可能会降低。相比之下，特应性皮炎的犬的血浆维生素E浓度低于健康个体。用维生素E治疗可显著提高特应性皮炎犬的血浆维生素E水平和总抗氧化能力。这些发现可能表明AD患者体内维生素或矿物质平衡的改变。然而，对于这些营养素与人类和犬的AD之间的关系，我们知之甚少。
No evidence was found for the use of niacinamide as antipruritic drug in atopic dogs. In nonallergic IMIDs, niacinamide commonly is used as anti-inflammatory drug. Currently, there are no published studies addressing possible anti-inflammatory effects of niacinamide in atopic dogs. In allergic humans, niacinamide is used mainly as topical agent. It has been shown to improve the skin barrier function by reducing trans-epidermal water loss. It would be interesting to further explore potential beneficial effects of niacinamide in cAD.
没有证据表明在特应性皮炎犬中使用烟酰胺作为止痒药。在非过敏性IMIDs中，烟酰胺通常用作消炎药。目前，还没有发表的研究涉及烟酰胺对特应性皮炎犬可能的抗炎作用。在过敏人群中，烟酰胺主要用作外部用药。它已被证明可以通过减少跨表皮水分流失来改善皮肤屏障功能。进一步探讨烟酰胺在CAD中的潜在y优势将是有趣的。
Autoimmune skin disease
自体免疫皮肤病
Minor evidence was found for the beneficial use of niacinamide in combination with cyclic antibiotics in dogs with superficial pemphigus and (generalised) DLE. By contrast, no evidence was found for its use in dogs with MCLE, VCLE and ECLE.
少量证据表明，烟酰胺联合循环抗生素对患有浅表性天疱疮和(全身型)DLE的犬有益。相比之下，没有证据表明它用于患有MCLE、VCLE和ECLE的犬。
The most commonly reported adverse effect associated with the use of niacinamide was gastrointestinal signs. In human dermatological practice, this combination of drugs has been used as adjunctive therapy to conventional treatment in pemphigus, as steroidsparing agent in pemphigus or as alternative therapy in bullous pemphigoid.However, to the best of the authors' knowledge, no data are available on its use in humans with CLE. The different pathogenesis of these autoimmune skin diseases and clinical heterogeneity of CLE might explain the difference in effectiveness. In addition, it would be of interest to further investigate efficacy of niacinamide without the use of cyclic antibiotics in the context of antibiotic resistance.
与使用烟酰胺相关的最常见的副反应是胃肠道症状。在人类皮肤病学实践中，这种药物组合已被用作天疱疮常规治疗的辅助治疗，用作天疱疮的类固醇节省剂或作为大疱性类天疱疮的替代治疗。然而，据作者所知，没有关于CLE患者使用该药物的数据。这些自体免疫性皮肤病的不同发病机制和CLE的临床异质性可能解释了疗效的差异。此外，在抗生素耐药性的背景下，进一步研究烟酰胺在不使用全身性抗生素的情况下的疗效将是有趣的。
Based on the results on the use of EFAs in general, no evidence was found for its use in dogs with superficial pemphigus and CLE variants. In comparison, treatment with omega-3 FAs in humans with autoimmune conditions shows conflicting results and no specific reports on the use of EFAs in humans with pemphigus or CLE have been found.
基于EFAs的一般使用结果，没有发现其用于患有浅表性天疱疮和CLE亚型的犬的证据。相比之下，在自体免疫性疾病患者中使用omega-3 FAs的治疗显示出相互矛盾的结果，并且没有发现在天疱疮或CLE患者中使用EFAs的具体报告。
No evidence was found either for the use of vitamin A, E, zinc or retinoids in dogs with CLE. The use of these nutraceuticals in canine CLE has hardly been researched. Interestingly, systemic retinoids (e.g. acitretin or isotretinoin) are recommended as second-line treatment for humans with refractory CLE and verrucous LE, a hyperkeratotic variant of DLE.
没有证据表明在CLE犬中使用维生素A、E、锌或维甲酸。这些营养品在犬CLE中的应用研究很少。有趣的是，全身性维甲酸(如阿维A酸或异维甲酸)被推荐作为难治性CLE和疣状LE(一种过度角化型DLE)的二线治疗。
Mainly, lower category studies were found with various descriptive results, small number of dogs included (especially for ECLE and VCLE) and often with the concurrent use of immunosuppressive drugs. In many studies, various treatment protocols in different disease stages were used, complicating assessment of efficacy of the used nutraceuticals.
主要是较低类别的研究发现了各种描述性结果，包括少量的犬(特别是ECLE和VCLE)，并且通常同时使用免疫抑制药物。在许多研究中，在不同的疾病阶段使用了各种治疗方案，使所使用的营养品的疗效评估复杂化。
Immune-mediated skin disease
免疫介导性皮肤病
Only minor evidence was found for the beneficial use of EFAs (mostly EPA and DHA with vitamin E) and niacinamide with cyclic antibiotics in dogs with SLO. No evidence was found for the use of vitamin B complex (B1, B2 and B6), biotin and zinc in SLO.
只有很少的证据表明，在患有SLO的犬中，EFAs(主要是EPA和DHA与维生素E)和烟酰胺与全身性抗生素的使用是有益的。没有发现维生素B复合物(B1, B2和B6)、生物素和锌在SLO中的使用证据。
Various treatment protocols have been used. Niacinamide and cyclic antibiotics are often combined with or followed by EFA supplementation. Despite the unknown aetiology of SLO, multiple possible causes or attributing factors have been reported, including adverse food reaction, interface onychitis and bacterial infection. Complete remission with systemic antibiotic therapy only also has been described. Interestingly, there are some dogs with a good response to initial therapy and no recurrence for longer periods of time without treatment. These findings and a somewhat waxing-and-waning nature of SLO, make assessment of clinical efficacy of treatment more difficult.
已经使用了各种治疗方案。烟酰胺和全身性抗生素通常与EFA补充联合或随后使用。尽管SLO病因不明，但多种可能的病因或归因因素已被报道，包括食物副反应、界面性甲床炎和细菌感染。仅采用全身抗生素治疗也有完全缓解的报道。有趣的是，有一些犬对最初的治疗有很好的反应，在没有治疗的情况下，长时间没有复发。这些发现和SLO的起伏性质使得评估临床治疗效果更加困难。
In dogs with SA, minor evidence was found for the beneficial use of retinoids (isotretinoin and etretinate), yet no evidence was found for beneficial use of zinc or vitamin A as monotherapy. The efficacy and associated therapeutic index differ between vitamin A and its synthetic analogues. For example, isotretinoin and etretinate are, respectively, 2.5- and 10-fold more potent than tretinoin. This may explain the difference in efficacy seen between retinoids and vitamin A in dogs with SA. Finally, no evidence was found for the beneficial use of EFAs in dogs with SA. Different protocols for SA treatment have been used, whereby topical therapy with antiseborrhoeic shampoos and moisturising products often were combined with systemic therapy including EFAs and ciclosporin. In the study by Lortz et al., improvement of clinical signs of alopecia and scaling was found with topical therapy only. For this reason, the clinical improvement seen in the retrospective studies found could be partly a result of the use of concurrent topical therapy. Based on the clinical signs and inflammatory component of this disease, a combination of omega-3 and omega-6 FAs with anti-inflammatory effects (EPA, DHA and GLA) and additional LA for skin barrier support may be of benefit. However, currently there is no scientific evidence to support this.
在SA患犬中，很少有证据表明使用维甲酸(异维甲酸和依维替酯)有益，但没有证据表明使用锌或维生素A作为单一疗法有益。维生素A与其合成类似物的疗效和相关治疗指标不同。例如，异维甲酸和依维替酯的药效分别是维甲酸的2.5倍和10倍。这可能解释了维甲酸和维生素A在SA患犬上的疗效差异。最后，没有证据表明EFAs对SA患犬有益。SA治疗使用了不同的方案，其中抗皮脂溢香波和保湿产品的外部治疗通常与包括EFAs和环孢素在内的全身治疗相结合。在Lortz等人的研究中，发现仅用外部治疗就能改善脱毛和皮屑的临床症状。因此，在回顾性研究中发现的临床改善可能部分是同时使用外部治疗的结果。基于这种疾病的临床症状和炎症成分，具有抗炎作用的omega-3和omega-6 FAs (EPA, DHA和GLA)和用于皮肤屏障支持的额外LA的组合可能有益。然而，目前还没有科学证据支持这一点。
CONCLUSIONS
结论
In the management of cDIMIDs, nutraceuticals are often used as monotherapy or adjunctive treatment. However, major supportive evidence could not be found. There is minor evidence for beneficial effects of several nutraceuticals in some diseases and no evidence for others (Table 2a-b).
在cDIMIDs的治疗中，营养品常被用作单一治疗或辅助治疗。然而，没有找到主要的支持性证据。有少量证据表明几种营养品对某些疾病有优势，而对其他疾病则没有证据(表2a-b)。
In order to confirm the beneficial effects of nutraceuticals in the treatment of cDIMIDs, double-blinded, randomised, placebo-controlled standardised studies with larger number of dogs are needed to support their use. For the practical use of nutraceuticals, it also is important to distinguish between initial and maintenance therapy, and to compare efficacy as monotherapy or adjunctive treatment.
为了证实营养品在治疗cDIMIDs中的有优势，需要对大量犬进行双盲、随机、安慰剂对照的标准化研究来支持其使用。对于营养品的实际使用，区分初始治疗和维持治疗，并比较单一治疗或辅助治疗的疗效也很重要。
过敏性皮肤病 |
营养品 |
使用剂量 |
单药（M）或联合治疗（A） |
临床结果 |
最短疗程 |
参考文献证据类型 |
必需脂肪酸（EPO） |
540-720mg/kg0.75EPO/天 |
M |
过敏性瘙痒患犬皮肤发红明显改善 |
9周 |
I |
（1）商品化Omega-3FA或（2）亚麻油 |
1:110mg/kg0.75EPA 75mg/kg0.75DHA/天 2:200-335mg亚麻油/kg，550mg/kg0.75ALA，150mg/kg0.75LA/天 |
A |
所有补充剂的皮肤和瘙痒评分有明显改善 |
10周 |
I |
商品化Omega-3FA和Omega-6FA |
25-50mg/kg0.75LA 15-30mg/kg0.75GLA 1.5-3mg/kg0.75DHA/天 |
A |
64天后泼尼松龙使用剂量明显降低（例：药物节省作用）；84天后瘙痒和；临床评分明显降低 |
9周 |
I |
商品化Omega-3FA和Omega-6FA（1:3.75） |
65-100mg/kg0.75ALA 70-110mg/kg0.75EPA 45-70mg/kg0.75DHA及未知LA等/天 |
A |
环孢素剂量明显降低例：（药物节省作用） |
12周 |
I |
Lactobacillus sakei probio-65 |
1g（2*109cfu）/天/<5kg） 2g（4*109cfu）/天/>5kg） |
M |
瘙痒明显改善 |
8 |
I |
商品化热杀粪肠球菌FK-23菌株 |
1g<10kg 2g10-20kg 3g20-30kg |
A |
病变评分明显降低 |
12 |
I |
Lactobacillus paracasei K71 |
5mg/kg/天 |
A |
药物评分明显降低（例：药物节省作用） |
12 |
II |
超微PEA |
10.9mg/kg范围（6.4-25中间值10.7）/天 |
M |
瘙痒、皮肤病变、生活质量评分明显改善 |
8 |
III |
维生素D |
300-1400IU/kg/天 |
A |
瘙痒和皮肤评分明显改善 |
8 |
I |
维生素E（α-生育酚） |
8.1IU/kg/天 |
A |
皮肤评分明显改善 |
8 |
I |
蛋氨酸锌 |
1.6mg/kg锌元素/天 |
A |
使用环孢素或泼尼松龙治疗患犬皮肤病变评分明显下降； 使用泼尼松龙治疗患犬搜啊杨评分明显下降 |
12 |
II |
未完继续
| 
|Archiver|手机版|小黑屋|宠医帮
( 京ICP备2022012070号-2 ) 
发表于 2023-3-27 21:19:41
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