影响犬猫马皮肤黑色素细胞的自体免疫疾病---（1）白癜风

王帆

Autoimmune diseases affecting skin melanocytes in dogs, cats and horses: vitiligo and the uveodermatological syndrome: a comprehensive review

影响犬、猫、马皮肤黑色素细胞的自体免疫疾病：白癜风和葡萄膜皮肤病综合证综述

作者：Heng L. Tham, Keith E. Linder and Thierry Olivry

翻译：侯宁 校对：王帆

Abstract

Autoimmune dermatoses targeting melanocytes have gained attention in human medicine due to their progressive nature and the social impact suffered by affected individuals. In veterinary medicine, vitiligo and the uveodermatological syndrome are the two autoimmune diseases that are known to affect skin melanocytes. In the first part of this article, we will review the signalment, clinical signs, histopathology and the treatment outcome of vitiligo in dogs, cats and horses; where pertinent, we compare the animal diseases to their human homologue. In a similar fashion, the information on the uveodermatological syndrome in dogs is reviewed and, where relevant, it is compared to the Vogt-Koyanagi-Harada (VKH) syndrome in humans. Canine, feline and equine vitiligo have many features that mirror their human counterparts. The most effective treatment and outcome of vitiligo in animals remain unclear. The canine uveodermatological syndrome resembles the incomplete VKH variant in humans; for affected individuals, an immediate diagnosis and aggressive treatment are crucial to prevent the development of blindness.

Keywords: Autoimmune skin diseases, Vitiligo, Uveodermatological, Vogt-Koyanagi-Harada, Leukoderma, Depigmentation, Melanocytes, Canine, Feline, Equine, Dermatology

摘要       

由于不断恶化的病情和患者所遭受的社会压力，针对黑色素细胞的自体免疫性皮肤病在人医中备受关注。在兽医领域，白癜风和葡萄膜皮肤病综合证是已知的会影响皮肤黑色素细胞的两种自体免疫性疾病。在本文的第一部分，我们将回顾犬、猫及马白癜风的特征、临床症状、组织病理学和治疗结果；在相关部分，我们将其与人类相关疾病进行了比较。我们用类似的方法回顾了犬葡萄膜皮肤病综合证，并将其与人类的小柳原田综合征（VKH）进行比较。犬、猫、马白癜风有许多特点都与人类似。对于动物白癜风最有效的治疗方法和效果尚不清楚。犬葡萄膜皮肤病综合证类似于人的不完全性VKH；对于患病个体，及早诊断和积极地治疗对于预防失明非常重要。

关键词：自体免疫性皮肤病、白癜风、葡萄膜皮肤病综合证、小柳原田综合征、白皮症、色素减退、黑色素细胞、犬、猫、马、皮肤病学

Background

背景

Melanocytes possess the unique ability to synthesize melanin pigments, which contribute to the skin and hair color of humans and animals. Other than the skin and skin appendages of domesticated mammals, melanocytes are found in the oral mucosa, eye, cochlea and less consistently the meninges . In the eyes, melanocytes are abundant in the uvea (i.e., the iris, ciliary body and choroid); the uveal pigment is thought to protect the retina from an overexposure to solar radiation and its resulting damaging affects. In the ear, melanocytes are found in the stria vascularis of the cochlea and contribute to endolymph formation.

黑色素细胞具有合成黑色素的独特能力，对人和动物的皮肤及毛发的颜色有着重要影响。除了家养哺乳动物的皮肤和皮肤附件外，黑色素细胞还存在于口腔黏膜、眼睛、耳蜗和少量存在脑膜中。在眼内，黑色素细胞大量存在于葡萄膜中（如虹膜、睫状体和脉络膜）；葡萄膜色素被认为可以保护视网膜免于太阳辐射过度的照射及其产生的破坏性影响。在耳内，黑色素细胞存在于耳蜗管的血管纹中，有助于内淋巴液的产生。

Autoimmune diseases of melanocytes have gained attention in human medicine due to their often-progressive nature and the negative social impact suffered by affected individuals. These diseases are due to the specific destruction of melanocytes, which results in a variety of clinical presentations, depending on the organ(s) in which the melanocytes are targeted. In vitiligo, signs associated with the destruction of melanocytes are limited to the skin, lips and/or oral cavity. In contrast, in the Vogt-Koyanagi-Harada (VKH) syndrome, they are more diverse because of involvement of the skin, lips, oral cavity, eyes, meninges and/or auditory system.

由于病情经常发生恶化，且对患者造成了很负面的社会影响，人医十分重视黑色素细胞的自体免疫性疾病。在该疾病中由于黑色素细胞的特异性破坏会出现各种各样的临床症状，这取决于黑色素细胞的靶器官。白癜风中，与黑素细胞破坏相关的症状仅限于皮肤、嘴唇和/或口腔。与此不同的是小柳原田综合征（VKH）涉及的器官包括皮肤、嘴唇、口腔、眼睛、脑膜和/或听觉系统，所以有多种临床表现。

In this review, we will focus on the two recognized autoimmune disease of melanocytes in animals: vitiligo and the uveodermatological syndrome, the canine homologue of the VKH disease of humans.

在这篇回顾中，我们会重点介绍目前动物中已知的两种黑色素细胞自体免疫性疾病：白癜风和葡萄膜皮肤病综合证，与人VKH疾病同源的犬类疾病。

Vitiligo

白癜风

Introduction

介绍

Vitiligo is defined as an acquired, chronic, depigmentation disorder characterized by white patches, often symmetrical in humans, corresponding to a substantial loss of functional epidermal and sometimes hair follicle melanocytes. The term vitiligo was first used in the Latin medical classic ‘De Medicina’ during the second century (cited in). There are different opinions on the origin of the word vitiligo: while some state that the depigmentation resembles the white glistening of the flesh of calves (in Latin, calf is ‘vitulus’ with ‘vituli’ its plural), others believed that the term vitiligo is derived from the Latin word ‘vitium’, meaning defect or blemish.

白癜风定义为一种以白色斑片为特征的获得性、慢性、色素减退性疾病，在人类中通常表现为对称性，相当于表皮层和一些毛囊内黑色素细胞的功能严重丧失。白癜风一词最早出现在二世纪拉丁医学经典著作“De Medicina”。关于白癜风这个词的起源有着不同的意见：有些人认为这种色素减退类似于新鲜牛犊肉的的白色反光（拉丁语中，小牛是“vitulus”，“vitui”是复数形式），其他人认为白癜风一词来源于拉丁语词汇“vitium”，意思是缺陷或污点。

Herein, we review the relevant information published to date on the canine, feline and equine vitiligo and we compare it with that published on the human disease homologue, where appropriate.

本文回顾了迄今为止已发表的关于犬、猫和马白癜风的文章，并与人类的类似疾病中已发表的信息进行比较。

Historical perspective

历史回顾

Vitiligo in humans was first described more than 1500 years BC. In ancient times, vitiligo was confused with leprosy and other depigmenting disorders, and it resulted in a discrimination and social stigma that, unfortunately, still persists today. It is only in the last century that vitiligo has gained more interest in the field of medical research.

人白癜风最早发现于公元前1500年。在古代，白癜风和麻风病及其他色素减退性疾病混淆，会遭到歧视和社会耻辱，不幸的是这种现象至今仍存在。直到上个世纪，白癜风才在医学研究领域得到更多的重视。

The first case series of vitiligo in dogs was reported in 1971. Seven years later, two articles were published: one as a case report in the proceedings from a human dermatology meeting in Geneva, and the other as a prospective study that collected data via a questionnaire and reported three clinical cases; the latter article was the first to detail the clinical, histological and electron microscopic features of vitiligo in 38 dogs.

第一例犬的白癜风报道于1971年。七年后，有两篇文章发表：一篇是发表于日内瓦人类皮肤病学会议论文集中的病例报告，另一篇是一项前瞻性研究，通过调查问卷进行数据收集，并报道了三例临床病例；后一篇文章首次介绍了38只白癜风犬的临床症状、组织学特征及电镜下特点。

Reports on feline vitiligo are even rarer than those of the canine disease: the first published case reports of feline vitiligo were both in 1986, although this disease was likely recognized earlier. The most detailed report on feline vitiligo (in a Siamese cat) was published in 1994.

猫白癜风的报道比犬更罕见：猫白癜风病例首次报道于1986年，虽然该疾病的出现要更早。关于猫白癜风（暹罗猫）最详尽的报道发表于1994年。

In the horse, Duerst was cited to have first mentioned the term vitiligo in 1931 (cited in), but it was not until the 1960s when Meijer, a Dutch veterinarian, reported equine vitiligo in three separate papers; of note is that the horses in the 1965 report might be the same as those included in the papers published in 1961 and 1962.

在马中，1931年Duerst第一次引用白癜风一词，但直到20世纪60年代，荷兰兽医Meijer分别在三篇论文中报道了马白癜风；值得注意的是，1965年的报道中的马可能和1961年1962年文章中的马是同一匹马。

Incidence and prevalence

发病率和患病率

Vitiligo is the most common depigmenting disorder in humans, with a prevalence estimated at approximately 0.5–2.0% of the world population; it has been reported to be as high as 8.8% in India. The disparity between prevalence and incidence could be due to the demographics from which the data originated (e.g., it might be estimated to be higher in dark skinned populations in whom lesions are more prominent).

白癜风是人类最常见的色素减退性疾病，发病率大概占全世界人口的0.5%-2%；在印度的发病率要更高为8.8%，其流行性和发病率间存在差异，可能由于人口统计的数据来源问题（例如黑色人种的病变更加明显所以其发病率可能被高估）。

There are no available data to estimate the global or regional incidence and prevalence of vitiligo in dogs, cats or horses. However, at Cornell University, Scott and Miller reported that vitiligo accounted for 0.7% of equine dermatoses examined at the veterinary teaching hospital. The prevalence of vitiligo in animals may be much higher than that reported, however, because this disease is a primarily cosmetic issue in animals, and it might not motivate owners to seek any veterinary care.

目前还没有数据可以用来评估全球或地区内犬、猫或马白癜风的发病率和流行性。然而，康奈尔大学Scott和Miller报道称在兽医教学医院马的皮肤病检查中白癜风占0.7%。但动物中白癜风的发病率要比报道的高的多，由于该病主要是动物的美观问题，主人可能并没有急切的需求想要寻求兽医的帮助。

Etiopathogenesis

发病机理

Most of the information available about the etiopathogenesis of vitiligo derives from results of studies performed using human samples. The three main hypotheses are biochemical, neural and autoimmune. Other review papers suggested the adhesion defect and oxidative theories, even though the latter overlaps with the biochemical hypothesis. Of these theories, the autoimmune hypothesis is the leading one, as it is derived from studies that showed that antibodies directed against melanocytes were more prevalent in animals and humans with vitiligo. Other studies also showed the involvement of the innate immune system (natural killer cells and inflammatory dendritic cells) and cytotoxic CD8+ T lymphocytes. This explains why most interventions for the treatment of vitiligo in humans are centered around immunosuppressive therapies. In a recent review, the convergence theory posits that a combination of various pathways is involved in the development and progression of vitiligo. These mechanisms, in addition to the aforementioned, included genetic susceptibility, mechanical stress and associated Koebnerization (i.e., trauma-induced lesions), psychological stress, reduced melanocytes antioxidant defenses, microbial dysbiosis and aberrant melanocytes-keratinocyte intercellular communication, which all intertwined in a yet-unknown mechanism leading to the loss of melanocytes from the skin. A recent theory attempts to explain this convergence mechanistically: an oxidative cellular stress would not only injure melanocytes but also induce novel autoantigens, or expose cryptic cellular antigens, which would then activate an immune response against melanocytes to promote lesion development. Additional factors, (e.g., genetic, environmental, etc.) could then influence both mechanisms of oxidative injury and immunological responses, thus explaining the multifactorial nature of the disease.

大多数关于白癜风发病机理的信息都来自对人样本的研究。主要的三种假说分别是生物化学、神经和自体免疫。其他综述类文章中提出粘附缺陷和氧化理论，尽管后者和生物化学假说存在重叠。在这些理论中，自体免疫假说是其中最重要的假说，研究表明在患有白癜风的动物和人中针对黑色素细胞的抗体更为普遍。其他研究也证明了先天免疫系统（自然杀伤细胞和炎性树突状细胞）和细胞毒性CD8+T淋巴细胞的参与。这也解释了为何人医对于白癜风的治疗都集中于免疫抑制疗法。在最近的一篇综述中，趋同理论认为，白癜风的发生和进展与多种途径相结合有关。除上述机制外，这些机制还包括遗传易感性、机械应激和相关的科波纳现象（koebnerization）（如创伤性病变）、心理应激、黑色素细胞抗氧化能力下降、微生物失调和黑色素细胞和角化细胞间的细胞通讯异常，在未知的机制中这些因素交织在一起导致皮肤黑色素细胞的丢失。最近的一种理论试图从机制上解释这种趋同机制：氧化细胞应激不仅会损伤黑色素细胞，也会诱导产生新的自身抗原，或暴露隐性的细胞抗原，从而激活针对黑色素细胞的免疫反应，促进病变的发展。其他因素（如基因、环境等）也会影响氧化损伤和免疫应答机制，也就解释了该疾病的多因素性。

In 1986, Naughton and colleagues reported the detection of antibodies to surface antigens of pigmented cells in 24 animals with vitiligo. In that study, serum was collected from 28 Belgian Tervueren (17 with vitiligo), seven Siamese cat (four with vitiligo) and six Arabian horses (three with vitiligo). Using immunoprecipitation and immunofluorescence assays and human pigmented melanoma cells previously shown to express vitiligo antigens, all animals with vitiligo had circulating antibodies to a surface antigen of pigmented cells, whereas none of those from normal animals had such antibodies. The authors suggested that the pathogenesis of vitiligo in man and animals was similar because both appeared to have a similar abnormal antibody response to pigmented cells. However, since then, to the authors’ knowledge, there have been no new studies on the pathogenesis of vitiligo in animals, thus limiting the advancement of mechanisticbased treatment and outcome assessment.

1986年，Naughton和他的同事报道了针对24只白癜风动物色素细胞表面抗原的抗体检测的研究。在该研究中，收集了28只比利时特弗伦犬（17只患有白癜风），7只暹罗猫（4只患有白癜风）和6匹阿拉伯马（3只患有白癜风）的血清。使用免疫沉淀和免疫荧光分析方法，人黑色素瘤细胞预先表达白癜风抗原，所有白癜风动物都具有针对色素细胞表面抗原的循环抗体，这种抗体并不存在于正常动物中。作者认为，白癜风的发病机制在人和动物中是相似的，因为似乎都有相似的异常的抗体反应的色素细胞。然而从那时起，剧作者所知，在动物中还没有针对白癜风发病机制的新研究，从而限制了基于此发病机制的治疗方法及预后的进展。

Signalment

特征描述

In humans, vitiligo affects both genders equally. It can develop at any age, but 70–80% of cases arise before the age of 30 with an onset before the age of 12 years being common (up to 37% of patients in one study).

在人类中，白癜风没有性别差异。任何年龄都可能发病，但70%-80%的病例在30岁前发病，常见12岁前发病（在一项研究中发病率高达37%）。

In the dog, rottweiler and doberman pinscher dogs (in the USA) as well as collies are thought to be predisposed to vitiligo. In the present review, the breeds reported with canine vitiligo are derived from 12 publications including 74 dogs. Among these cases, there were 38 Belgian Tervuerens (51%), 15 rottweilers (20%), seven Labrador retrievers (9%), three German shepherd dogs (4%), two old English sheepdogs (3%) and Beauceron shepherd dogs (3%) and one each (1%) of the following breeds: giant schnauzer, miniature dachshund, Newfoundland, Bernese mountain dog, Collie and a mixed breed dog. From the nine case reports in which information on the sex was available, the female-to-male ratio was 1.0. The mean and median ages of onset were 26months and 24 months, respectively (range: 2 months to 11 years).

在犬中，罗威纳犬和杜宾犬（美国）及柯利犬都是白癜风的高发品种。在目前的综述中，犬白癜风的报道有12篇，包括74只犬。在这些病例中，包括38只比利时特弗伦犬（51%），15只罗威纳犬（20%），7只拉布拉多犬（9%），3只德国牧羊犬（4%），2只古代英国牧羊犬（3%）和法国牧羊犬（3%），及以下品种各一只（1%）：巨型雪纳瑞犬、迷你腊肠犬、伯恩山犬、柯利犬和已知杂交品种犬。在9例性别已知的病例中，雌性与雄性比为1.0。发病的平均年龄和中位年龄分别为26个月和24个月（范围：2月龄至11岁）。

There are four reports of feline vitiligo including seven cats. Of these, six were Siamese, and one was a European mixed breed. The sex was only reported for three cats: two females and one male. The age of onset was only reported in one Siamese, and it was 21 months.

有四份关于猫白癜风的文章包括7只猫。其中6只暹罗猫，一只欧洲杂交品种猫。其中只有三只猫性别已知：2只雌性1只雄性。仅报道了一只暹罗猫的发病年龄，为21月龄。

The breeds of horses affected with vitiligo can be inferred from five reports including 32 horses. Among these cases, there were 12 Gelderlands (38%), nine Spanish thoroughbreds (28%), four Arabians (13%) and Belgians (13%) and one each (3%) of the following breeds: Oldenburg, Mecklenburg and quarter horse. The breeds that were reported by Meijer in two reports published in 1961 and 1962 were not considered because we are unsure if the reported horses were the same reported in the 1965 paper. The sex of the affected horses was available from three reports with 28 horses of which the female-to-male ratio was 2.1. Vitiligo is reported to be common in Arabian horses(the so-called “Arabian fading syndrome” and “pinky Arab”) and there are numerous references listing this breed in review papers, equine text books and the lay literature. The published information is however limited and thus it may not completely represent the commonality of equine breeds affected by vitiligo, which are different in the literature and appear to vary by geographical location. The age of onset was only reported in seven horses with a median of 48 months (range: 1 to 18 years).

从5篇包含32匹马的文章中可以推断马是白癜风的易感品种。在这些病例中包括12匹盖尔德兰马（38%），9匹西班牙纯种马（28%），4匹阿拉伯马（13%）和比利时马（13%），及以下马种各一匹（3%）：奥尔登堡马、梅克伦堡马、奎特马。Mejier在1961年和1962年发表了两篇文章，其中的品种并没有列入其中，因为无法确定文章中的论文是否与1965年文章中的马相同。在三篇28只马匹的论文中报道了患病马匹的性别，其中雌性与雄性的比例为2.1。白癜风在阿拉伯马中很常见（所谓的“阿拉伯衰退综合征”和“粉红阿拉伯”），在综述文章、马的教科书和文献中列出了大量该品种的参考文献。然而已发表的文章很有限，所以不能完全代表白癜风的马匹品种，与文献的报道存在差异，且受地理因素发生变化。发病年龄仅在7匹马中有报道，中位年龄为48个月（范围1-18年）。

Clinical signs

临床症状

In humans, vitiligo is classified clinically into segmental (SV) and non-segmental variants (NSV), with the latter including three major subsets: generalized, acrofacial and universal vitiligos. Other variants are mixed and unclassified vitiligo (focal and mucosal vitiligo). The initial lesions of NSV in humans usually arise on areas exposed to chronic traumas, especially on the hands or the arms, a feature attributed to the Koebner phenomenon . According to a recent international consensus conference, NSV is characterized by depigmented macules of varying sizes, which usually spare the scalp and haired regions, although hair depigmentation may occur with disease progression. The loss of hair pigmentation can follow the depigmentation of the skin but rarely precedes it; there is one case series of follicular vitiligo described in humans. Depigmentation of the iris and retina are seen in a minority of patients with vitiligo (reviewed in).

在人中，临床上将白癜风分为节段型（SV）和非节段型（NSV），后者包括三个主要的亚型：全身型、肢端型和泛发性白癜风。其他还包括混合型和未分型白癜风（局灶型和黏膜型白癜风）。根据科波纳现象的特点，人NSV的原发病变通常发生于慢性创伤部位，特别是手和手臂。根据最近一份国际共识，NSV定义为大小不等的色素减退斑点，通常头皮和有毛区域，但随着病情的发展头发可能会出现色素减退。头发色素缺减退可能在皮肤色素减退之后发生，但很少会先出现。在人中，有一类病例称为毛囊型白癜风。在少数白癜风病例中可见虹膜和视网膜的色素减退。

In dogs, information on the location of the first lesion(s) of vitiligo was available from seven reports including 55 patients. In most dogs, depigmented macules and/or patches initially developed on the face and were more often multifocal than focal. The gingiva and lips were the two most commonly affected regions and the depigmentation sometimes progressed from multifocal to complete oral depigmentation. As the disease progressed, depigmented lesions were confined to the face and/or head in most dogs and involved one or more of the following regions: eyelids, eyelashes, nasal planum, oral cavity (hard palate and buccal mucosa), pinnae and muzzle (Fig. 1). However, the depigmentation also developed at other locations such as the footpads, scrotum, nails/claws, paws/limbs and the neck/trunk/ rump region. Generalized depigmentation (Fig. 2) was reported in two dogs, with the former case only affecting black hair. Bilaterally symmetrical lesions were only reported in three dogs in one case report.

在犬中，从7例病例报道的55只动物中得到关于白癜风原发病变的发病部位的信息。大多数犬中，色素减退的斑点和/或斑片原发于面部，多灶性比局灶性的更常见。齿龈和嘴唇是最常见的感染部位，有时局灶性的色素减退会发展为整个口腔的色素减退。随着病情的发展，大多数犬中，色素减退病变仅限于头面部，包含以下一个或多个部位：眼睑、睫毛、鼻平面、口腔（硬颚和颊黏膜）、耳廓和嘴周（图1）。然而，色素减退也可见于其他部位如爪垫、阴囊、甲/爪部、脚掌/四肢和颈部/躯干/臀部。两只犬报道为全身性色素减退（图2），第一个病例中病变仅见黑色被毛。仅在一篇三只犬的病例报道中提到对称性病变。

The rare form of follicular vitiligo resembles the case reported by White and Batch, where all seven Labrador retriever puppies only exhibited leukotrichia without leukoderma.

毛囊型白癜风这种罕见形式与White和Batch的报道类似，7只拉布拉多犬只表现为白毛症未见白皮症。

Fig. 1 Canine vitiligo. a 5-year-old Airedale terrier with a 2-month history of fairly-symmetrical depigmented patches on the nasal planum (courtesy of Dr. F. Banovic, case material NCSU). b 4-year-old Australian shepherd with a 3-month history of rapidly-progressing depigmentation (leukoderma) of the nasal planum and lips; hair depigmentation (leukotrichia) was also present on the head (courtesy of Dr. HL Tham, case material NCSU). c 4-year-old Bernese Mountain dog with periocular depigmentation; this dog also had leukotrichia that progressed to generalized poliosis (courtesy of Dr. L. Beco). d 2-year-old Rottweiler with periocular leukoderma and leukotrichia (courtesy of Dr. E. Guaguère). e same dog as in (a); depigmentation of the footpad (courtesy of Dr. F. Banovic, case material NCSU). f same dogs as in (d): partial depigmentation of the claw (courtesy of Dr. E. Guaguère)

图1 犬白癜风。a:：5岁的万能㹴，2个月鼻平面对称性色素减退病史。b:4岁澳大利亚牧羊犬，3个月鼻平面和嘴唇快速渐进性色素减退（白皮症），同时也可见于头部毛发色素减退（白毛症）。c：4岁伯恩山犬，眼周色素减退；也存在白毛症并发展为全身性白毛症。d： 2岁罗威纳犬，眼周白皮症和白毛症。e：与a为同一只犬；爪垫色素减退。f：与d为同一只犬：爪部局部色素减退。

Fig. 2 Canine vitiligo. a Australian shepherd with a normal coat color. b Eight months later, there was generalized skin, hair and iris depigmentation due to vitiligo; the owner confirmed the iris depigmenting as the coat color changed (courtesy of Dr. K. Pantenburg )

图2 犬白癜风。a：一只毛色正常的澳洲牧羊犬。b：8个月后，因为白癜风导致全身皮肤、被毛和虹膜色素减退，主人称虹膜随着被毛颜色改变而改变。

Interestingly, Mahaffey and colleagues reported that four dogs had focal depigmentation of the outer surface of the lower lip at the point contacted by the maxillary canine tooth. Whether this clinical feature was associated with a Koebner phenomenon or trauma-induced hypopigmentation is not known but the adhesion defect theory (“melanocytorrhagy theory”) has been postulated as one of the pathogenesis of nonsegmental vitiligo in humans. Based on the clinical distribution of lesions in dogs, most cases of canine vitiligo resemble those of the acrofacial subset of NSV, which is the most common form of vitiligo in humans, at least during the initial course of the disease.

有趣的是，据Mahaffey和他的同事报道，有四只犬的下嘴唇的外表面与犬上颌牙接触处有局灶性色素减退。这种临床特征是否与科波纳现象或创伤引起的色素减退有关尚不清楚，但粘附缺陷理论（“噬黑色素细胞菌理论”）被认为是人类非节段型白癜风的发病机理之一。根据犬病变的临床分布，大多数犬白癜风类似人NSV的肢端型，是人最常见的白癜风类型，至少是在疾病的最初发病阶段。

Human vitiligo has been associated with autoimmune thyroid disease, systemic lupus erythematosus and Addison disease, among others. These are autoimmune diseases, that may have affected the melanocytes as “innocent bystanders”. Sunitinib, a tyrosine kinase inhibitor is associated with skin depigmentation and leukotrichia in humans. Vitiligo is also reported in humans with the Vogt-Koyanagi-Harada syndrome. The association of canine vitiligo with the canine uveodermatological syndrome (Vogt-Koyanagi-Harada-like syndrome) is discussed below in this review.

人白癜风与自体免疫性甲状腺疾病有关，尤其是系统性红斑狼疮和阿迪森病。这些自体免疫疾病可能会影响到“无辜的旁观者”黑色素细胞。舒尼替尼是一种酪氨酸激酶抑制剂，与人皮肤色素减退和白发病相关。白癜风在人小柳原田综合征中也有报道。本综述将在下面讨论犬白癜风与犬葡萄膜皮肤病综合征（类小柳原田综合征）的关系。

Interestingly, out of 12 canine case reports of vitiligo, two were reported to have a concurrent systemic disease (diabetes mellitus and primary hypoadrenocorticism). One additional case was linked to the administration of toceranib phosphate. In the study by Mahaffey and colleagues, one dog developed hypopigmentation shortly after dexamethasone treatment for demodicosis, another was reported to have irregular estrus cycle and a third dog had a history of pancreatitis. In the dogs of the remaining reports, systemic illnesses were not described.

有趣的是在，在12例犬白癜风病例报道中，2例并发全身性疾病（糖尿病和原发性肾上腺皮质功能减退）。另有一例病例与使用磷酸托拉尼布（帕拉丁）有关。Mahaffey和同事的研究表明，一只犬在使用地塞米松治疗蠕型螨病后不久出现了色素减退，另一只犬据报道发情周期不规律，第三只犬有胰腺炎病史。在其他报道中没有提及全身症状。

In cats, only one report described the locations of the first skin lesions and depigmentation occurred on the nasal planum, periocular area and footpads (Fig. 3). In three cats, the distribution of lesions were available and the nasal planum/nose was affected in three cats and the footpad(s) in two. Although there are few case reports, this facial-predominant depigmentation in feline vitiligo is similar to what has been reported in dogs. In one cat, depigmentation (both leukoderma and leukotrichia) was localized before progressing toward generalization. Systemic illness was not reported in any of these cats.

对于猫只有一份病例报告描述了首次发现的皮肤病变的部位和色素减退发生在鼻平面、眼周和爪垫（图3）。3只猫的病变分布不同，3只猫都有鼻平面/鼻部病变，2只出现爪垫病变。虽然病例报道很少，猫白癜风中以面部为主的色素减退与犬报道类似。在一只猫中，在发展为全身性病变之前为局灶性色素减退（白皮症和白毛症）。在其他病例中没有全身性疾病的报道。

Information of the first skin lesion(s) were available for six horses, all of which initially having developed depigmentation on the head/face region. The lesion distribution was reported in 11 horses, of which eight (73%) involved the head/face region (Fig. 4). Again, this facial-predominant distribution is similar to that of dogs and cats with vitiligo. However, interestingly, three out of 11 horses (27%) had leukotrichia and leukoderma on the neck, trunk and limbs without involvement of the face or head. Other than vitiligo, an acquired idiopathic leukotrichia, also known as spotted leukotrichia has been reported in horses, especially in thoroughbred, and Arabians. Horses with the so-called “spotted leukotrichia” have multifocal, well-circumscribed, small circular areas of near complete leukotrichia on otherwise normal skin on the neck, trunk and rump. However, to the authors’ knowledge, there are only sparse histologic details on this condition. It is plausible that this spotted leukotrichia is a variant of vitiligo in horses that tends to spare the face and head.

从六匹马中收集到原发性皮肤病变的信息，这些马的色素减退症状全部原发于头/面部。报道了11匹马的病变分布情况，8只（73%）出现头/面部症状（图4）。病变主要分布在面部，这与犬猫白癜风类似。然而有趣的是，11匹马中的3匹（27%）在颈部、躯干和四肢出现白皮症和白毛症，而不包括头面部。与白癜风不同，另一种获得性特发性白毛症，也称为斑点性白毛症，在马中也有报道，特别是纯种马和阿拉伯马。患有所谓斑点性白毛症的马，在颈部、躯干和臀部的正常皮肤上有多灶性、边界清晰的小的圆形的，几乎完全白毛表现。然而与作者所知，这种疾病仅有稀少的组织学细节描述。这种斑点性白毛症是一种马白癜风类型，倾向于波及面部和头部毛发。

Histopathology

组织病理学

The key histological feature of vitiligo (Fig. 5) in all animal species is the loss of melanocytes from the epidermis and/ or hair follicle. The epidermal architecture is normally retained but keratinocytes lack melanosomes (pigment granules) in fully developed areas. Melanosomes are spilled to the superficial dermis (pigmentary incontinence), and sometimes the hair follicle peribulbar area, where they are incorporated in melanophages. Minimal-to-mild numbers of lymphocytes are often present in the basal epidermal layer, especially near the junction of pigmented and nonpigmented epidermis; here lymphocytes are rarely observed adjacent to apoptotic melanocytes (“satellitosis”). Lymphocytes are thought to indicate an active disease state with the cell-mediated destruction of melanocytes. Dermal infiltrates of inflammatory cells, lymphocytes, plasma cells, and histiocytes are minimal or inflammation can be completely absent, then suggesting an inactive disease stage. In the latter situation, histology does not easily differentiate vitiligo from normal white “spots”, but this dilemma can be resolved with the clinical history. Due to the cosmetic nature of the disease, the diagnosis is often made clinically without any need for skin biopsies. If biopsies are to be taken, then multiple samples are ideally collected from the depigmented margins of recently active lesions, especially if erythema were present and indicative of dermal inflammation.

在所有动物中白癜风的主要组织学特征（图5）为表皮层和/或毛囊黑色素细胞的丧失。在病变部位表皮层结构保持正常，但角质形成细胞在发育完全的部位丧失色素小体（色素颗粒）。色素小体有时会扩散到真皮浅层（色素失禁），有时还会扩散到毛囊毛球周围，与噬黑色素细胞结合。表皮基底层通常存在极少量到少量的淋巴细胞，特别是在表皮层有色素和无色素的交界处附近；此处罕见淋巴细胞与凋亡的黑色素细胞相邻（卫星现象）。淋巴细胞提示疾病处于活跃状态伴有细胞介导的黑色素细胞损伤。炎性细胞、淋巴细胞、浆细胞和组织细胞的真皮层浸润很少，或者完全没有炎性浸润，表明疾病的不活跃阶段。后一种情况难以区别白癜风与正常的白色“斑点”，但可以通过临床症状进行鉴别。由于该病影响美观，通常无需组织活检临床即可诊断。如果进行皮肤活检，最理想的是从目前活跃病变的色素减退边缘采集多个样本，特别是存在红斑并提示皮肤炎症反应。

Fig. 3 Feline vitiligo. a and b Siamese cat with vitiligo affecting the nasal planum and footpads (courtesy of Dr. Z. Alhaidari)

图3.猫白癜风。a 和b 暹罗猫白癜风感染鼻平面和脚垫（Dr. Z. Alhaidari提供）

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Fig. 4 Equine vitiligo. a and c Quarterhorse with multifocal depigmented macules on the lips, muzzle, face and peri-ocular area (courtesy of Dr. J. Davis). b Horse with only a large, unilateral, depigmented patch below the right eye (courtesy of Dr. J. Davis). d 1-year-old Swedish warmblood stallion with coalescing leukodermic macules and patches of the lips (courtesy of Dr. K. Bergvall)

图4.马白癜风。a 和c 夸特马嘴唇黏膜、嘴周、面部和眼周多灶性色素减退。b 只有右眼下方一处大的、单侧的脱色性斑片。d .1岁的瑞典温血种马，嘴唇有连成片的白色斑点和斑片。

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Fig. 5 Histopathology of canine vitiligo. In a skin biopsy from the face, lymphocytes infiltrate the basal layer of the epidermis (arrow heads) in very low numbers at the junction of depigmented and non-depigmented epidermis. Melanin containing macrophages are present in low numbers in the superficial dermis (arrow) and are accompanied by a very mild, mononuclear, perivascular, inflammatory cell infiltrate. The epidermal architecture is not significantly altered. Hematoxylin and eosin. 200X

图5犬白癜风组织病理学。面部皮肤活检，在表皮层色素减退区域与非色素减退区域的交界处的表皮基底层（箭头）有极少量淋巴细胞浸润。在真皮浅层（箭头）有少量含有黑色素的巨噬细胞，在血管周围伴有轻微的单核细胞炎性浸润。皮肤表皮层结构未见明显改变。HE染色。200倍

Treatment and outcome

治疗和效果

In humans, due to the heterogeneity in the designs of clinical trials and often-small numbers of participants, there is no firm clinical recommendation for the treatment of vitiligo. This disease has a devastating psychological impact on the quality of human life, as do psoriasis and atopic dermatitis. This may explain why treatment of widespread, facial or recalcitrant vitiligo in humans can be aggressive.

在人中，由于临床试验的设计的异质性，且参与者数量通常很少，所以没有关于治疗白癜风的明确临床建议。该病会对摧毁人的心理健康从而影响人的生活质量，银屑病和特应性皮炎也是如此。这就解释了为什么人们会积极地治疗广泛性、面部或顽固性白癜风。

The Vitiligo Guideline Subcommittee of the European Dermatology Forum outlined the management of NSV based on four levels. The first-line therapy involves narrow band UVB (NB-UVB) radiation whereas treatment escalation involves the use of systemic glucocorticoids (GCs). In non-responding areas, especially those with high cosmetic impact, surgical grafting with the aim to replace the melanocytes with those from a normally pigmented autologous donor site is recommended as the third-line therapy. Finally, in patients with extensive and refractory vitiligo, depigmentation techniques (hydroquinone monobenzyl ether or 4-methoxyphenol) is proposed as the fourth-level treatment. In limited NSV (less than 2–3% of body surface), topical GCs or calcineurin inhibitors and localized NB-UVB radiation are proposed as the first- and second-line therapies, respectively. In humans, acrofacial vitiligo (‘lip-tip’ vitiligo) is resistant to treatment, as does a appear the canine disease homologue. Oral and topical JAKinibs, such as tofacitinib, are currently under investigation as mono- or adjuvant therapy for this disease.

欧洲皮肤病论坛白癜风指南小组委员会将NSV的管理概述为四级。一级治疗包括窄波紫外线（NB-UVB）辐射，二级治疗包括糖皮质激素的全身治疗（GCs）。在治疗无效部位，特别是严重影响美观的部位，通过手术将色素正常部位的皮肤进行自体移植替换黑色素细胞，这种治疗被作为三级治疗。最后在患有泛发性和顽固性白癜风的患者中，脱色素技术（对苯二酚单酶醚或4-甲氧基苯酚）被作为第四级治疗方法。在限制型NSV中（小于体表面积的2-3%），外用糖皮质激素或钙调神经磷酸酶抑制剂和外部NB-UVB辐射作为为一级和二级治疗方案。人中，肢端型白癜风（“唇指”白癜风）治疗效果不好，似乎是犬的同类疾病。口服和局部外用的JAK激酶抑制剂，如托法替尼，目前正在研究将其作为该病的单一或辅助用药。

In dogs, reports detail a variety of treatments for vitiligo with variable outcomes. These treatments included ammoidin (xanthotoxin) with solar exposure, psoralens with ultraviolet light, systemic glucocorticoids, adrenocorticotrophic hormone (ACTH) injections, doxycycline-niacinamide and thyroid supplementation, L-phenylalanine, vitamin and mineral supplementation, and diet change. Treatments that resulted in the complete or almost complete repigmentation were psoralens and ultraviolet light, as well as ammoidin and solar exposure, respectively. In another report, L-phenylalanine (a tyrosine precursor) for 6 months resulted in 75% clinical improvement in four dogs. Vitamin and mineral supplementation and diet change resulted in partial repigmentation in some dogs but not others. Adrenocorticotrophic hormone injections over a 3-month period only resulted in a temporary slight improvement in one dog but the depigmentation relapsed when the ACTH injections were stopped. In another dog, a change of environment was suspected to lead to partial repigmentation of the nasal planum and gingiva over several months. Spontaneous remission was reported in two Belgian Tervuerens, a litter of seven Labrador retrievers, and a Bernese mountain dog. In the latter breed, a spontaneous remission occurred 3 weeks after treatment with toceranib phosphate for mast cell tumour was stopped.

在犬中，文章详细描述了白癜风的不同治疗方法和治疗效果。治疗包括氧化补骨脂素（花椒毒素）配合日光照射，补骨脂素配合紫外线照射，给予全身性糖皮质激素，注射促肾上腺皮质激素（ACTH），使用多西环素-烟酰胺和补充甲状腺素，L-苯丙氨酸，补充维生素和矿物质，以及改变日粮。治疗后发生完全或几乎完全色素改变的是使用补骨脂素和紫外线照射，和氧化补骨脂素配合日光照射。在另一篇文章中使用L-苯丙氨酸（一种酪氨酸前体）6个月后在4只犬中75%有临床的改善。补充维生素和矿物质及改变日粮使部分犬的色素得到改善，其他犬无效。注射促肾上腺皮质激素3个月仅一只犬出现了暂时性的轻度改善，并在停药后复发。另一只犬中，怀疑几个月后环境的改变导致其鼻平面和牙龈色素的改善。据报道在2只比利时特弗伦犬、同窝7只拉布拉多犬和1只伯恩山犬中出现了自发性色素改善。在另一品种中，使用磷酸托拉尼布（帕拉丁）治疗肥大细胞瘤3个月停药后出现自愈。

In cats, there are no reports detailing the treatment and outcome of vitiligo. Spontaneous repigmentation, albeit only partial, on the concave and convex surfaces of the pinnae, was reported in one case 40 months after initial onset.

在猫中，没有详细描述猫白癜风治疗和疗效的文章。在一篇病例报道中描述了一例初始发病40个月后，在耳廓的内外侧出现局部自发性的色素改善。

Treatment and outcome data for 11 horses were available from three reports indicating it took between one to 12 months for significant repigmentation to occur. Complete repigmentation occurred in one horse treated with oral nutritional supplements containing, among others, vitamin A, D, B12 and E. In another report, partial repigmentation occurred after supplementation with high levels of chelated copper. A relapse of depigmentation occurred approximately 5 months after the copper supplementation was reduced and then a noticeable clinical improvement occurred when the daily intake of copper was re-increased. It is plausible that the depigmentation in this horse was associated with a copper deficiency and not vitiligo. Nine horses from one case report had complete repigmentation after 1 year of dietary supplementation with carrots (4–5 kg/animal/day). The author suspected that the administration of high levels of thyroprotein-based product might have caused a relative vitamin A deficiency and depigmentation. However, to the authors’ knowledge, there is no evidence that vitamin A deficiency leads to depigmentation in horses but, in humans, several studies have shown that deficiencies of D and B12 vitamins are associated with vitiligo. Therefore, the outcome of these nine horses of this report should be interpreted cautiously. A plausible cause could have been an idiosyncratic reaction to high levels of a thyroprotein-based product, or any of its ingredients, as the cessation of this diet led to spontaneous resolution.

从三篇文章中得到11匹马的治疗和疗效的资料，资料表明色素减退的改善需要1-12个月。其中1匹马口服含有维生素A、维生素D、维生素B12和维生素E的营养补充剂后色素减退完全改善。另一篇报道中在使用高剂量螯合铜制剂后发生部分色素改善。在铜补充剂剂量减少5个月后出现色素减退复发，之后重新增加每日铜摄入量临床症状明显改善。这匹马的色素减退似乎与铜缺乏有关而非白癜风。在一份病例报道中9匹马经过1年的日粮补充胡萝卜（4-5kg/只/天）后色素减退完全改善。作者怀疑大量碘化蛋白质产品的摄入可能导致维生素A的缺乏和色素减退。然而，据作者所知，没有研究表明白癜风和维生素D、维生素B12缺乏有关。因此，该报道中9匹马的治疗结果需要谨慎解读。对大量碘化蛋白产品或其他成分的特异性反应似乎是一个合理的解释，因为停止饲喂这些日粮后发生了自愈。

Information on the long-term treatment and outcome of vitiligo in animals is rather sparse, unfortunately, as there are only few published case reports to date.

遗憾的是，由于迄今为止已发表的病例报道极少，关于动物白癜风长期治疗和治疗结果的信息非常少。

Implications for practice

临床意义

Vitiligo is a cosmetic issue in animals. Therefore, any treatment for this disease should always be discussed with the owners to avoid interventions of dubious efficacy and those with possible adverse effects. However, vitiligo could have a significant and negative impact for the owners of show animals. In these, the application of topical GCs of high potency (i.e., 0.1% bethamethasone or 0.05% clobetasol) may be attempted on the affected skin, which would only be practical for areas with sparse or no hair; this recommendation is based on the assumption that the pathogenesis of vitiligo in humans and animals is similar and involves an autoimmune mechanism. For areas that have both leukoderma and leukotrichia, the hairs can be clipped to facilitate the penetration of topical GCs into the skin. To avoid localized side-effects of this drug class (e.g., skin atrophy, telangiectasias), the frequency of their application should be tapered to the lowest possible effective one. Topical GCs are still the mainstay of treatment for localized forms of vitiligo in humans. Topical calcineurin inhibitors, such as tacrolimus, offer an alternative to GCs, and, in humans, topical tacrolimus is recommended to be applied twice daily for the first 6 months.

白癜风关乎动物的美观问题。因此与该病有关的任何治疗都应该与动物主人讨论以避免可疑疗效和可能出现的副作用。然而白癜风可能对动物主人产生巨大的负面影响。可以在患病皮肤上外用强效GCs（如0.1%的倍他米松或0.05%的氯倍他索），仅适用于毛发稀疏或无毛部位；这种治疗建议是基于人和动物白癜风的发病机理相同，并与自体免疫机制有关。对于同时有白皮症和白毛症的区域，剃毛可促进皮肤对GCs的吸收。为了避免药物的局部副作用（如皮肤萎缩、毛细血管扩张），应逐渐减少用药频率至最低有效剂量。外部GCs的使用仍是人类治疗白癜风的主要治疗方法。外用钙调神经磷酸酶抑制剂如他克莫司，可以作为GCs的替代药物，在人中，建议前6个月外用他克莫司一天两次。

Systemic therapy, such as oral or parenteral GCs, is not normally recommended for treatment of vitiligo because the adverse effects outweigh the clinical benefits in animals. If topical therapy were to fail, oral supplementation with L-phenylalanine could be attempted for 6 months, although the clinical remission could be only partial. This supplementation might be tried in addition to the use of topical GCs.

通常不推荐使用全身治疗来治疗白癜风，如口服或肠外给予GCs，因为在动物中其副作用大于临床效果。如果外部治疗失败，可以尝试口服补充L-苯丙氨酸6个月，虽然可能只有部分缓解作用。也可以外用GCs的同时尝试补充L-苯丙氨酸。

It is important to emphasize to the owners that these treatments, if effective, may prevent the progression of depigmentation but they do not guarantee the partial or full repigmentation.

需要向主人强调，如果治疗有效会阻止色素减退的发展，但不能保证出现局部或完全好转。

Implications for research

研究意义

Only two reports of vitiligo in animals had information on their pedigree. In humans, the incidence of vitiligo is higher in those with family history of such disease. It may be worthwhile to perform another study similar to that of Mahaffey and colleagues but at a larger scale (i.e., multicentric study), involving more breeds around different continents to gather more information on the genetic predisposition to vitiligo in animals. This could be followed by a genomic wide-associated study to assess if any variant of vitiligo in some breeds is associated with a single trait. In humans, DDR1, XBP1, NLRP1 and PTPN22 genes have been linked to vitiligo and these genes could be a starting point to investigate if animals with vitiligo are linked to the genes and mutations reported in humans.

在动物白癜风的报道中，仅有2篇报道记录了血统信息。在人中，有家族病史的发病率较高。开展另一项类似于Mahaffey和其同事的研究可能很有意义，但其规模更大（如多中心研究），涉及不同大洲的更多品种动物，以收集更多关于动物白癜风遗传信息的资料。随后可以进行基因组相关的广泛研究，以评估在一些品种中任何白癜风的变异品种是否与单一性状有关。在人中，DDR1、XBP1、NLRP1和PTPN22基因可能与白癜风有关，这些基因可能作为研究动物白癜风与人类已报道的基因突变的联系的起点。

Phototherapy with NB-UVB is considered one of the most effective and safest treatment for vitiligo in humans, as it results in better repigmentation rates, between 40 and 100%. Interestingly, the dogs that had a complete or an almost complete remission of signs had received a form of phototherapy. Therefore, phototherapy treatment, either alone or in combination with other drugs, warrants further clinical trials in animals.

由于NB-UVB光疗法的色素恢复率能达到40%-100%，所以他是人类治疗白癜风最有效和最安全的方法之一。有趣的是，病情完全或几乎完全改善的犬接受过光疗法。因此单独的光疗法或联合其他药物的治疗需要更进一步的动物临床试验。

In humans, the autoimmunity of vitiligo is driven by the interferon-gamma-CXCL10 cytokine signaling pathway, which involves the activation of Janus kinases (JAK) 1 and 2. Oral ruxolitinib, a JAK inhibitor with JAK 1 and 2 inhibitory effect, resulted in rapid repigmentation in one man with coexistent vitiligo and alopecia areata. This led to an open-label, phase 2, proof-of-concept clinical trial to investigate the efficacy of topical ruxolitinib 1.5% as a treatment of vitiligo. Should this clinical trial report a noticeable degree of efficacy, it may be worthwhile performing a pilot study with JAK inhibitors in animals with vitiligo. A recent study of topical tofacitinib application in dogs reported anti-inflammatory effect on the skin and therefore, topical JAK inhibitors could potentially be an emerging treatment for various inflammatory diseases in animals. The use of oral JAK inhibitors deserves further investigation, at least in dogs with vitiligo.

在人中，白癜风的自体免疫是由干扰素-γ-CXCL10细胞因子信号通路介导，涉及Janus激酶JAK1和2的激活。一名患有白癜风和斑秃的男性口服鲁索替尼，一种具有JAK1和2抑制作用JAK激酶抑制剂，色素减退症状迅速恢复。因此开展了一项双盲，第二阶段概念验证临床试验，以研究外用1.5%鲁索替尼治疗白癜风的疗效。如果这项临床试验疗效显著，那么在白癜风动物中进行JAK抑制剂的试点研究相当有价值。最近一项犬外用托法替尼的研究表明其对皮肤具有抗炎作用，因此外用JAK抑制剂可能成为治疗各种动物炎性疾病的新型治疗方法。口服JAK抑制剂需要进一步研究，至少在犬的白癜风中如此。

Lastly, clinical and histological features of spotted leukotrichia in horses should be gathered and examined to determine if this condition is a variant of vitiligo, or a separate disease condition.

最后，应收集马斑点样白毛症的临床和组织学特征，并确定这种病变是否是白癜风的变异，或是一种单独的疾病。

假如是只四脚兽

似乎不影响犬的寿命

夏常宁

Ryohei

haohao