猫特应性皮肤综合征的治疗-系统性回顾（1）

王帆

Treatment of the feline atopic syndrome – a systematic review

猫特应性皮肤综合征的治疗-系统性回顾

作者：Ralf S. Mueller* , Tim Nuttall† , Christine Prost‡, Bianka Schulz* and Petra Bizikova§

翻译：王帆

Background – Feline allergic skin disease and asthma occur regularly in small animal practice.

Objectives – To provide evidence-based recommendations for small animal practitioners on the treatment of feline atopic syndrome (FAS).

Methods and materials – The authors reviewed the literature available before February 2020, prepared a detailed evidence-based literature review and made recommendations based on the evaluated evidence.

Results – Sixty-six papers and abstracts were identified describing treatment interventions for FAS and evaluated to establish treatment recommendations. For many treatment options, the papers were retrospective, open studies or case reports.

Conclusion and clinical relevance – In this review, there was good evidence for the efficacy of systemic glucocorticoids and ciclosporin, and limited evidence for the efficacy of topical glucocorticoids, oclacitinib and allergenspecific immunotherapy in feline atopic skin syndrome. Evidence pointed to low-to-moderate efficacy for antihistamines, fatty acids and palmitoyl ethanolamide. In feline asthma, there was good evidence for the efficacy of oral and inhaled glucocorticoids, and limited evidence of moderate efficacy for allergen-specific immunotherapy. Evidence supported low-to-moderate efficacy of mesenchymal stem cells, inhaled lidocaine and oclacitinib as treatments for feline asthma. For almost all therapeutic options (with the exception of glucocorticoids and ciclosporin), more randomised controlled trials are needed.

摘要

背景-猫过敏性皮肤病和哮喘在小动物临床非常常见。

目的-为小动物临床医生提供治疗猫特应性综合征(FAS)的有证据支持的治疗建议。

方法与材料-作者回顾了2020年2月之前的文献，准备了一份详细的循证文献综述，并根据评估的证据提出建议。

结果-明确了66篇描述FAS治疗管理措施的论文和摘要，并对其进行评估以确定治疗建议。对于许多治疗方案，论文是回顾性的、开放的研究或病例报告。

结论与临床意义-在这篇综述中，证据表明全身性使用糖皮质激素和环孢素的疗效好，而外用糖皮质激素、奥拉替尼和过敏原特异性免疫治疗对猫特应性皮肤综合征的疗效证据有限。有证据表明抗组胺药、脂肪酸和十六酰胺乙醇的疗效低到中等。在猫哮喘中，口服和吸入糖皮质激素的疗效证据充分，而过敏原特异性免疫治疗的疗效中等的证据有限。有证据支持间充质干细胞、吸入利多卡因和奥拉替尼治疗猫哮喘的疗效低至中等。对于几乎所有的治疗选择(糖皮质激素和环孢素除外)，都需要更多的随机对照试验。

Introduction

介绍

Feline atopic syndrome (FAS) is the newly-proposed terminology encompassing allergic diseases of the skin, gastrointestinal and respiratory tract in the cat. Feline atopic skin syndrome (FASS) describes allergic skin disease associated with environmental allergies. Allergic dermatitis in the cat presents with multiple cutaneous reaction patterns that all may be caused by environmental, food and/or insect allergens, as well as other diseases. Those reaction patterns include miliary dermatitis, self-induced alopecia/hypotrichosis, the eosinophilic granuloma complex (eosinophilic granuloma, eosinophilic plaque, indolent ulcer) and/or excoriations-ulcers on the head and neck. Consequently, the treatment of these reaction patterns will depend on their aetiology, and other causes such as food allergy or flea bite hypersensitivity must be ruled out before diagnosing FASS. Feline asthma is a common lower airway inflammatory condition in cats with significant morbidity and occasional mortality. From a clinical and pathogenetic point of view, feline asthma is remarkably similar to the human disease. As in humans, affected cats exhibit a spontaneous and natural hyper-reactivity of the airways resulting in a reversible bronchoconstriction, airway inflammation and chronic remodelling. Intradermal and serum testing for allergenspecific immunoglobulin (Ig)E is not suitable for the diagnosis of FAS. Similar to dogs, the FASS is diagnosed based on the history, clinical signs and exclusion of differential diagnoses appropriate to each case. Over the last decades, different treatments have been reported for FAS variants, yet to the best of the authors’ knowledge, a systematic review of all available therapeutic and preventive interventions has not been published. The aim of this review was therefore to summarise and review the published evidence for the various treatment options for the cutaneous and respiratory components of FAS. It was not within the remit of this paper to discuss the aetiology, pathogenesis and diagnosis of these diseases. These subjects are reviewed in other papers in this series and readers are directed to them for more information.

猫特应性综合征(FAS)是一个新提出的术语，涵盖了猫的皮肤、胃肠道和呼吸道的过敏性疾病。猫特应性皮肤综合征(FASS)描述了与环境过敏原相关的过敏性皮肤病。猫的过敏性皮肤病有多种皮肤反应模式，这些都可能是由环境、食物和/或昆虫过敏原，以及其他疾病引起的。这些反应模式包括粟粒性皮炎、自损性脱毛/少毛症、嗜酸性肉芽肿综合征(嗜酸性肉芽肿、嗜酸性斑块、无痛性溃疡)和/或头颈部抓痕性溃疡。因此，治疗这些反应模式将取决于其病因学，诊断FASS必须排除其他病因，如食物过敏或跳蚤叮咬过敏。猫哮喘是一种常见的猫下呼吸道炎性疾病，具有显著的发病率和偶尔的死亡率。从临床和病理的角度来看，猫哮喘与人类的疾病非常相似。和人类一样，患猫表现出自发和自然的呼吸道过度反应，导致可逆性支气管收缩、气道炎症和慢性重塑。皮内和血清检测过敏原特异性免疫球蛋白(Ig)E不适合诊断FAS。与犬一样，FASS的诊断是基于病史、临床症状和排除适合每个病例的鉴别诊断。在过去的几十年里，关于FAS各种不同治疗方法已被报道，但就作者所知，尚未发表对所有可用的治疗和预防措施的系统综述。因此，本综述的目的是总结和回顾已发表的关于FAS皮肤和呼吸道的各种治疗方案的证据。这些疾病的病因、发病机制和诊断不属于本文的研究讨论范围。这些主题在本系列的其他论文中进行了评论，读者可以直接到它们获得更多的信息。

Methods and materials

材料和方法

In order to evaluate the efficacy and safety of treatments for the two main FAS manifestations (FASS and asthma), online bibliographic databases (PUBMED and WEB OF SCIENCE) and scientific meeting proceedings were searched for relevant published studies or abstracts of sufficient detail for analysis. The bibliographies of identified studies and of main veterinary dermatology textbooks were further evaluated. Studies were analysed and their value determined based on the quality of their evidence (QOE). They were summarised and, based on the available data, a given treatment’s efficacy was determined and its reported adverse effects listed. Thereafter a recommendation about each treatment option was given, with the strength of recommendation (SOR) based on the QOE (Table 1). Data evaluation and strength of recommendations were modelled after previous practice guidelines for human and canine atopic dermatitis (cAD).

为了评估对两种主要FAS临床表现(FASS和哮喘)治疗的有效性和安全性，我们检索了在线书目数据库(PUBMED和WEB of SCIENCE)和科学会议记录，以寻找相关发表的研究或足够详细的摘要进行分析。进一步评估已确定的研究书目和主要的兽医皮肤病学教科书。对研究进行分析，并根据其证据质量(QOE)确定其价值。它们被总结，并基于现有的数据，确定一种给定的治疗效果，并列出其报告的副作用。随后给出了每个治疗方案的建议，推荐强度(SOR)基于QOE(表1)。数据评估和推荐强度是根据之前的人和犬特应性皮炎(cAD)临床指南为模型。

Results

结果

We found a total of 72 papers and abstracts describing treatment interventions for FAS. These included 58 clinical trials and eight case reports evaluating efficacy of treatments, five safety and pharmacokinetic studies in healthy cats, and one retrospective safety study (without reporting efficacy). Of the 55 clinical trials, six were available only as abstracts and 49 had been published in peer-reviewed journals. There were 48 prospective and 10 retrospective studies. Of the prospective studies, 19 were open and uncontrolled while 29 were randomised, controlled and often blinded.These studies included clinical trials on allergen avoidance, allergen(-specific) immunotherapy (ASIT), topical, inhaled and systemic glucocorticoids, ciclosporin, oclacitinib, bronchodilators, H1- receptor (H1R) antihistamines, essential fatty acids (EFA) and palmytoylethanolamide, antibiotics, inhaled lidocaine and mesenchymal stem cells. Thirty-three of the reports focused on the reaction patterns of FASS, while 23 studies evaluated feline asthma. Eleven of those latter studies originated from the same research group using cats experimentally sensitised to various allergens and five from another colony of cats sensitised to Ascaris suum. In some reports, cats with respiratory or cutaneous manifestations were included.

我们发现了72篇描述FAS治疗管理的论文和摘要。这些研究包括58项临床试验和8份评估治疗疗效的病例报告，5项安全性和药物动力学研究，以及一项回顾性安全性研究(没有疗效报告)。在55项临床试验中，6项仅作为摘要提供，49项已在同行评议的期刊上发表。其中前瞻性研究48项，回顾性研究10项。在前瞻性研究中，19项是开放和不受控制的，29项是随机、控制的，通常是盲法的。这些研究包括归避过敏原、过敏原(特异性)免疫治疗(ASIT)、局部、吸入和全身糖皮质激素、环孢素、奥拉替尼、支气管扩张剂、H1受体(H1R)抗组胺剂、必需脂肪酸(EFA)和十六酰胺乙醇、抗生素、吸入利多卡因和间充质干细胞的临床试验。其中33份报告关注于FASS的反应模式，23份研究评估了猫哮喘。后一项研究中，有11项来自同一个研究小组，研究对象是对不同过敏原敏感的猫，还有5项来自另一群对猪蛔虫敏感的猫。在一些报告中，包括有呼吸或皮肤临床表现的猫。

Allergen avoidance

规避过敏原

Analysis of evidence

证据分析

In one retrospective study of 29 asthmatic cats and one prospective study on 20 asthmatic cats, avoidance of allergens was reported for individual cases. We could not find any such evidence for FASS.

在一项针对29只哮喘猫的回顾性研究和一项针对20只哮喘猫的前瞻性研究中，个别病例报告了对过敏原的归避。我们没有为FASS找到任何这样的证据。

Analysis of efficacy

疗效分析

In the above-mentioned studies, one cat sensitised to human dander improved after access to the owner’s bedroom was restricted. Changing from dry food to a moist diet led to the complete remission of clinical signs in three cats allergic to storage mites.

在上述研究中，一只对人皮屑敏感的患猫在被限制进入主人的卧室后得到了改善。从干粮转变为湿粮，使对贮藏螨过敏的三只患猫的临床症状完全缓解。

Recommendations

推荐

Although allergen avoidance is common sense and should be effective (QOE 3; SOR C), it is often unfeasible in cats sensitised to environmental allergens. There is only limited evidence for the benefit of allergen avoidance in asthmatic cats,and no such information exists for FASS.

虽然避免过敏原是常识，且应该是有效的(QOE 3;SOR C)，但是对于对环境过敏原敏感的猫通常是难以实现的。只有有限的证据表明归避过敏原对哮喘患猫有效，而对FASS没有这样的信息。

ASIT

过敏原特异性免疫治疗

Analysis of evidence

证据分析

Eleven reports evaluated ASIT in a total of 197 cats with FASS. Five retrospective studies specifically evaluated ASIT in 70 cats with different reaction patterns of FASS. Seventeen cats had miliary dermatitis, 21 had noninflammatory alopecia, 18 had eosinophilic lesions and in one study the clinical signs were not detailed. Two of these reports were abstracts in proceedings from World Congresses of Veterinary Dermatology and thus not sufficiently detailed. Likewise, one prospective open study evaluating sublingual ASIT was a conference abstract. One report described the response to ASIT in three littermates with atopic skin disease, one case series described four cats with miliary dermatitis and eosinophilic granuloma, and another focused on rush immunotherapy (RIT) in four atopic cats, although treatment outcomes were not described in the latter report. One larger study was based on a questionnaire sent out by a laboratory after serum testing for allergen-specific IgE and subsequent orders for ASIT in 81 cats, six of which had lower respiratory tract disease.The last study evaluated 45 cats with FASS, 23 of which underwent AIT. Definitions of a good, moderate, partial or no response varied and often were unclear. In one study, an excellent response was described as complete remission of the patient with no concurrent medication and was seen in 26% of the cats. In the study using a survey sent out to veterinarians treating cats with ASIT after serum testing for allergen-specific IgE, lesional scores were assigned and the percentage of improvement calculated.In another study, concurrent medications were not discussed; in many reports concurrent medications were mentioned and details not given.

11份报告评估了总共197只FASS患猫的ASIT。五项回顾性研究专门对70只患有不同FASS反应模式的猫进行了ASIT评估。17只猫患有粟粒性皮炎，21只患有非炎性脱毛，18只患有嗜酸性病变，在一项研究中，临床症状不详。其中两份报告是世界兽医皮肤病学大会的摘要，因此不够详细。同样，一项前瞻性开放研究评估了舌下ASIT，它是一个会议摘要。一篇报道描述了3只患有特应性皮炎的同窝猫对ASIT的反应，一篇报道描述了4只患有粟粒性皮炎和嗜酸性肉芽肿的猫，另一篇报道关注了4只特应性皮炎患猫的冲击免疫治疗(RIT)，但是后者的报告中没有描述治疗结果。一项更大规模的研究是基于实验室在对81只猫进行血清过敏原特异性IgE检测和后续ASIT测试后发出的问卷，其中6只猫患有下呼吸道疾病。最后一项研究评估了45只FASS患猫，其中23只接受了AIT。良好、适度、部分或无反应的定义各不相同，而且常常不清楚。在一项研究中，在26%的患猫中没有服药但症状完全缓解。在这项研究中，在对ASIT治疗的猫进行血清过敏原特异性IgE测试后，向兽医发送了一份调查，对病变进行了评分，并计算了改善的比例。在另一项研究中，没有讨论联合用药;在许多报告中提到了同时服用的药物，但没有给出细节。

Five studies evaluated cats with respiratory disease/ asthma. In an older retrospective study, veteriarians submitting feline serum specimens for allergen-specific IgE testing were asked to complete a follow-up questionnaire, six cats with respiratory clinical signs undergoing ASIT were included. One study focussed on ASIT as treatment for 12 asthmatic cats showing sensitization to aeroallergens based on intradermal testing. Three studies were performed in an experimental model of feline asthma in which cats were sensitised to Bermuda grass and house dust mites. In the first randomised controlled trial (RCT), intranasal or subcutaneous RIT were compared. In a second study using the same model, cats received RIT with an allergen that they were not sensitised to or with only one of the two allergens they were sensitised to. The third study evaluated the influence of oral and inhaled glucocorticoids on the outcome of RIT. In one conference abstract, a cat with cutaneous and respiratory sign was treated with ASIT using a recombinant Der f 2- based vaccine.

五项研究评估了患有呼吸道疾病/哮喘的猫。在一项更早的回顾性研究中，兽医提交猫血清样本进行过敏原特异性IgE测试，并要求完成一份随访问卷，包括对6只有呼吸道临床症状的猫进行ASIT。一项研究集中于ASIT作为12只哮喘患猫的治疗，根据皮内测试显示对空气过敏原过敏。在猫哮喘的实验模型中进行了三项研究，猫对百慕大草和室内尘螨敏感。在第一个随机对照试验(RCT)中，比较了鼻内或皮下RIT。在另一项使用相同模型的研究中，猫接受了含有对它们不敏感的过敏原的RIT，或者只含有对它们敏感的两种过敏原之一。第三项研究评估口服和吸入糖皮质激素对RIT结果的影响。在一次会议摘要中，用基于Der f2的重组疫苗对一只有皮肤和呼吸道症状的猫进行了ASIT治疗。

Analysis of efficacy

疗效分析

The results of ASIT for FASS were reported in 210 cats (Table 2). The reported efficacy was between 45 and 75%, similar to what is reported for dogs. One of the studies did not evaluate treatment outcome, and looked only at the safety of RIT in four cats with FASS.

记录了210只FASS患猫ASIT治疗的结果(表2)。报告的有效率在45 - 75%之间，与对犬的疗效相似。其中一项研究没有评估治疗效果，只是在四只患有FASS的猫身上观察了RIT的安全性。

Results of ASIT in 80 cats with asthma are listed in Table 3. In one study a complete remission of clinical signs was observed in eight of 12 cats with naturally occurring asthma (67%) in which symptomatic therapy with glucocorticoids could be discontinued on ASIT. Four cats still required pharmacotherapy, including inhaled corticosteroids and bronchodilators. In a retrospective study, veterinarians treating 12 cats with suspected feline asthma reported a good response via questionnaire.

80只哮喘患猫的ASIT治疗结果列于表3。在一项研究中，12只自然发生哮喘的猫中有8只(67%)的临床症状完全缓解，ASIT可以停止糖皮质激素的对症治疗。四只猫仍然需要药物治疗，包括吸入糖皮质激素和支气管扩张剂。在一项回顾性研究中，兽医通过问卷对12只疑似哮喘患猫进行了治疗。

Three studies evaluated ASIT in cats with experimentally induced asthma. In the first RCT, intranasal or subcutaneous RIT improved clinical signs and dampened eosinophilic inflammation of the airways.However, intranasal RIT had fewer adverse effects and a decreased interleukin (IL)-4/interferon-gamma ratio in the bronchoalveolar lavage fluid (BALF). In the second study, airway eosinophilia decreased and the percentage of regulatory T cells and IL-10-producing cells increased in cats treated with RIT compared to controls independent of their sensitisation status and content of the allergen extract, indicating nonspecific effects. However, only matched allergens could potentially induce an immunological cure.In the same model of feline asthma, cats given oral prednisolone at 10 mg once daily over the first six months of ASIT showed an increased percentage of eosinophils in the BALF after nine months of ASIT by contrast with inhaled fluticasone at 220 mcg twice daily.

三项研究评估了实验性诱发哮喘患猫。在第一个随机对照试验中，鼻内或皮下RIT改善了临床症状，并抑制了气道嗜酸性细胞炎症梵音。然而，鼻内RIT副反应更少，且降低了支气管肺泡灌洗液(BALF)中的白介素(IL)-4/干扰素-γ比值。在第二项研究中，与对照组相比，RIT治疗的猫气道嗜酸性细胞减少，调节性T细胞和IL-10产生细胞的比例增加，这与它们的敏化状态和过敏原提取物的含量无关，表明了非特异性效应。然而，只有匹配的过敏原才能潜在地诱导免疫治疗。在相同的猫哮喘模型中，在ASIT的前6个月给猫口服10mg泼尼松龙，每天一次，在ASIT的9个月后，与吸入220mg的氟替卡松，每天两次的BALF中嗜酸性细胞的比例增加。

Adverse effects

副作用

Adverse effects were not mentioned in ten reports. After RIT, two of four cats showed increased pruritus and in two of four a dermal alopecic nodule developed one week after initiation of therapy.

10份报告中均未提及副反应。RIT治疗后，四只猫中的两只表现出瘙痒增加，四只猫中的两只在开始治疗一周后出现了皮肤脱毛性结节。

Recommendations

建议

ASIT seems to be an efficacious therapy for FASS (QOE 2; SOR B). However, some studies were presented only as abstracts with very limited information, none of the studies were controlled or randomised, and all were characterised by unclear outcome measures, making final assessment difficult. By contrast, there is evidence of moderate-to-good efficacy of ASIT in naturally occurring feline asthma (QOE 2; SOR B) and moderate efficacy of RIT in cats with experimental asthma (QOE 1; SOR A). Adverse effects seem to be rare (QOE 1; SOR A). More studies on ASIT in cats are needed urgently.

ASIT似乎能有效治疗FASS(QOE 2; SOR B)。然而，一些研究仅以信息非常有限的摘要形式呈现，没有一项研究是受控或随机的，所有研究的特征都是结果衡量标准都不明确，使得最终评估变得困难。相比之下，有证据表明ASIT对自然发生的猫哮喘有中度至良好的疗效(QOE 2; SOR B)，RIT对实验室诱发哮喘患猫的疗效中度(QOE 1; SOR A)。副反应似乎很罕见 (QOE 1; SOR A)。迫切需要对猫进行更多的ASIT研究。

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