影响犬猫马皮肤黑色素细胞的自体免疫疾病---（2）葡萄膜...

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

The uveodermatological syndrome

葡萄膜皮肤病综合证

Introduction

介绍

The uveodermatological syndrome (UDS) is a canine entity that resembles the VKH disease in humans; in UDS, dogs develop severe bilateral granulomatous posterior or panuveitis with retinal detachments, disk edema and vitritis; these may or may not be accompanied with the tinnitus, hearing loss, vertigo, meningitis, poliosis (patches of hair depigmentation or leukotrichia) and vitiligo seen in the human disease. Herein, we will review the available information published to date on the canine UDS, and where relevant, comparisons with the human homologue (VKH disease) are made. To the authors’ knowledge, UDS has not been reported in cats and horses.

葡萄膜皮肤病综合征（UDS）是犬中一种类似于人VKD的疾病；UDS的犬可发展为严重的双侧肉芽肿性后葡萄膜炎或全葡萄膜炎，伴有视网膜脱落、视盘水肿和玻璃体炎；这些在人类疾病中可能伴有或不伴有耳鸣、失聪、眩晕、脑膜炎、白发病（毛发斑块样色素减退或白毛症）和白癜风。在此，我们将回顾迄今为止发表的关于犬UDS的有用信息，并与人类相应疾病（VKH）进行比较。据作者所知，UDS在猫和马中还没有报道。

Historical perspective

历史回顾

More than a century ago, in 1906, a medical resident from Switzerland by the name of Alfred Vogt published a case report entitled “Premature whitening of eyelashes and comments about the so-called sudden onset of this change”. His paper focused mainly on poliosis (patches of white hair) and only briefly described uveitis. Seventeen years later and nearly 6,000 miles away, Einosuke Harada, reported nine cases of “acute diffuse choroiditis” between 1923 and 1926, which later was called Harada’s disease. Twenty-three years later, another Japanese ophthalmologist, Yoshizo Koyanagi wrote a review article that described in detail a disease including severe uveitis, poliosis, alopecia and dysacusis.

一个多世纪以前，在1906年，一位来自瑞士名叫Alfred Vogt的住院医生发表了题为“睫毛过早发白和发生这种变化的评论”的病例报告。他的论文主要集中在白发病（斑块状白发）上，仅简要介绍了葡萄膜炎。十七年后，将近6000英里外的Einosuke Harada报告了1923年至1926年间的9例“急性弥漫性脉络膜炎”病例，后来被称为原田病。二十三年后，另一位日本眼科医生Yoshizo Koyanagi撰写了一篇回顾文章，详细描述了一种包括严重的葡萄膜炎、白发病、脱发和听力减退的疾病。

In 1939, the Vogt-Koyanagi (VK) syndrome was first proposed for the disease reported by Vogt and Koyanagi. Although the disease reported by Harada greatly resembled that of the VK syndrome, it was not until the late 1950s that the term Vogt-Koyanagi-Harada (VKH) syndrome was used. In 2001, the term “disease” was finally selected by the International Committee on Nomenclature of VKH, but many papers published thereafter still used the term “syndrome”.

1939年，Vogt和Koyanagi首次报道Vogt-Koyanagi（VK）综合征。尽管Harada报道的疾病与VK综合征非常相似，但直到20世纪50年代后期才开始使用小柳原田（VKH）综合征这一术语。2001年，最终国际命名委员会将VKH命名为“疾病”一词，但此后发表的许多论文仍使用“综合征”一词。

In animals, a disease resembling the VKH syndrome was first reported in 1977 –coincidentally also in Japan. It was not until 1985 that the term “uveodermatological syndrome - UDS” was introduced into the veterinary literature by Romatowski. This author argued that the term “canine VKH syndrome” was inaccurate because the dogs reported did not seem to exhibit any meningeal involvement, and thus did not fit the inclusion criteria of the then human VKH syndrome. It is possible, however, that such neurological signs might have been underdiagnosed. Since then, the terms UDS and VKH-like syndrome have been used interchangeably in the veterinary literature.

在动物中，类似于VKH综合征的疾病首次报道于1997年-恰巧也在日本。直到1985年，Romatowski才将“葡萄膜皮肤病综合征-UDS”一词引入兽医学文献中。该作者认为，“犬VKH综合征”一词是不准确的，因为报道中的犬似乎未见脑膜病变，因此不符合当时人VKH综合征的标准。然而，有可能这些神经系统症状未被诊断出来。从那以后，在兽医学文献中术语UDS和VKH样综合征可互换使用。

Etiopathogenesis

发病机理

The exact etiology and pathogenesis of the VKH disease in humans remain unclear, but the general agreement is that it is an autoimmune disease that targets melanocytes or melanocyte-associated antigens (i.e., tyrosinase and gp100) with an increased susceptibility in populations with certain human leukocyte antigens (HLA). Indeed, several studies have shown a strong association of HLADRB1* 0405 and HLA-DQB1*0401 in patients with the VKH syndrome in China, Brazil, Korea and Saudi Arabia. Immunohistochemical studies have shown that 70% of the lesional lymphocytes were T cells and that the choroidal infiltrate was composed predominantly of helper T cells. Other studies showed that, in humans with this syndrome, tyrosinase peptide antigens are the target for autoimmune T cells. Altogether, these data support an autoimmune disease with cell-mediated immunity playing an important role in its pathogenesis.

人VKH的确切病因和发病机制仍不清楚，但普遍认为它是一种针对黑素细胞或黑素细胞相关抗原（即酪氨酸酶和gp100）的自体免疫性疾病，具有特定人类白细胞抗原（HLA）的人群的易感性增加。实际上，一些研究表明，在中国、巴西、韩国和沙特阿拉伯，VKH综合征患者中HLADRB1 * 0405和HLA-DQB1 * 0401抗原有很强的相关性。免疫组化研究表明，70%病变的淋巴细胞是T细胞，脉络膜的浸润主要是辅助T细胞。其他研究表明，在患有这种综合征的人中，酪氨酸酶肽抗原是自体免疫T细胞的目标。总之，这些数据表明在该病的发病机理中，细胞介导的自体免疫性疾病具有重要地位。

Interestingly, in some human patients, viral infections (i,e., the Epstein-Barr virus and the cytomegalovirus) have been hypothesized as possible triggering factors of this disease. This could be due to similarities between viral antigens and proteins from pigmented cells (molecular mimicry theory) . The role of antiretinal antibodies (ARAs) in the human VKH syndrome remains the matter of debate because the autoreactivity against retinal proteins seems to differ between acute and chronic disease and these antibodies could be a produced in response to the retinal damage. In addition to this syndrome, antiretinal antibodies have been also detected in other ocular diseases such as cancerassociated retinopathies, toxoplasmosis and age-related macular degeneration.

有趣的是，在一些患者中，假定病毒感染（如艾博斯坦-巴尔病毒和巨细胞病毒）是诱发该疾病的可能病因。这可能是由于病毒抗原与色素细胞蛋白质之间的相似性（分子模拟理论）。视网膜抗体（ARAs）在人VKH综合征中的作用仍然存在争议，因为在急性和慢性疾病中视网膜蛋白的自身反应性似乎不同，这些抗体可能是对视网膜损伤的反应。除了这种综合征外，还在其他眼部疾病中检测到抗视网膜抗体，如癌症相关的视网膜病，弓形虫病和年龄相关性黄斑变性。

In animals, the UDS likely also has an autoimmune basis. In one study, the dog leukocyte haplotype (DLA)-DQA1*00201 occurred at a higher incidence in American Akitas with UDS compared with normal unaffected dogs of the same breed; there was a significantly higher relative risk and odds ratio for the development of UDS compared to other DLA class II alleles. The injection of peptides derived from tyrosinase-related protein into rats and in two Japanese Akitas resulted in clinical signs resembling those of the human VKH syndrome. Similarly to humans, ARAs were detected in one dog using an ELISA that utilized bovine retinal extract as an antigen source. In that study, the serum from an Akita was positive for ARAs with a titer ≥1:200 (normal reference interval titers was reported to be between 1:25 and 1:50). Interestingly, when the disease was stable, the ARA titer decreased to 1:25 but increased to 1:200 when a relapse occurred. Although, this observation suggests that ARA titers might correlate with disease activity, it is not known if ARAs are the cause or sequela of a previously-active disease.

在动物中，UDS也可能具有自体免疫基础。一项研究表明，犬的白细胞抗原（DLA）- DQA1 * 00201在患有UDS的美国秋田犬中发生率高于同一品种的正常犬；与其他DLA II类等位基因相比，UDS的患病风险和发病率也更高。将来自酪氨酸酶相关蛋白的肽注射到大鼠和两个日本秋田犬中，结果产生了类似于人VKH综合征的临床症状。与人类相似，利用牛视网膜提取物作为抗原进行ELISA试验，在一只犬中检测到ARAs。在该研究中，秋田犬抗ARA阳性，血清滴度≥1：200（据报道正常参考区间1:25-1:50）。有趣的是，当疾病稳定时，ARA滴度降至1:25，但在复发时增至1：200。虽然，这一观察结果表明ARA滴度可能与疾病活动有关，但尚不清楚ARAs是否是病因或是疾病的后遗症。

Incidence and prevalence

发病率和患病率

In several recent review papers, the prevalence of the human VKH disease in North America is reported to be between 1 and 4% of patients, but these papers cite an old study published in 1977 that reported VKH to represent 1% of patients affected with uveitis. Therefore, the “true” prevalence of the VKH disease may be much higher now due to better awareness and access to medical services and advancement in diagnostic procedures.

在最近的几篇综述中，据报道在北美，人VKH的患病率为1％-4％，但这些论文引用了1977年发表的一项旧研究，该研究报道VKH占葡萄膜炎患者的1％。因此，由于对疾病的认识和医疗服务的不断提升以及诊断流程不断的进步，现在VKH的“真实”患病率可能要更高。

There are no available data to estimate the global or regional incidence or prevalence of the UDS in dogs. However, the canine UDS has a worldwide distribution and has been reported in dogs from Asia, Europe, South America and North America.

目前尚无数据可以估计犬UDS在全球或地区的发病率或患病率。犬UDS分布于世界各地，并且在亚洲、欧洲、南美和北美的犬中已有报道。

Signalment

特征描述

The human VKH disease predominantly affects people in their second-to-fifth decades of life, with a higher occurrence in female patients, but children as young as four-years-old also have been reported to be affected; it is more common in individuals with a pigmented skin.

人VKH疾病主要发病于20-50岁，女性的发病率更高，但据报道，4岁的儿童也可能会患病；深色肤色的人更易患病。

In dogs, Akitas, Samoyeds and Siberian Huskies are breeds suspected to be predisposed to the UDS, but this syndrome has been reported in other breeds as well. There are 38 articles that can be grouped for the detailed analysis of 166 dogs with the UDS. Among these cases, 110 (66%) were Akitas, 14 (8%) were Siberian Huskies and five (3%) were Samoyeds; other breeds only made up less than 3% each of the total number of affected dogs reported to date. The age of onset of this disease varied between 7months and 13 years of age (median: 3 years, mean: 3.6 years) while the female-to-male ratio was 0.6, thus suggesting that males are affected nearly twice as often as female dogs.

在犬中，秋田犬、萨摩犬和哈士奇犬可能是UDS的易感品种，但在其他品种也有该病的报道。有38篇文章中详细分析了166只USA患犬。在这些病例中，110只（66％）是秋田犬，14只（8％）哈士奇，5只（3％）萨摩犬；目前为止，其他品种犬只各占患犬总数不到3％。该病的发病年龄在7个月到13岁（中位发病年龄：3岁，平均发病年龄：3.6岁），而雌性与雄性的比例为0.6，这表明雄性的发病率几乎是雌性的2倍。

Clinical signs

临床症状

The human VKH disease is typically classified into four stages: prodromal, acute, chronic convalescent and chronic recurrent stages. The prodromal stage lasts from several days to a few weeks and it is characterized by flu-like symptoms such as headache, tinnitus, nausea, neck pain and back pain. The acute stage begins with the development of usually bilateral and posterior uveitis, and it is during this stage that the blurring of vision appears, and if untreated promptly, visual fields, color vision and central visual acuity can be compromised. The convalescent stage ensues several weeks-to-months after the acute stage, and it consists of signs of depigmentation of the uveal tissue and/or integument. Finally, in the chronic recurrent stage, a mild panuveitis with recurrent episodes of anterior uveitis occurs and this stage is considered the consequence of an inadequate or delayed treatment.

人VKH通常分为四个阶段：前驱期、急性期、慢性恢复期和慢性复发期。前驱期持续数天至数周，其特征为流感样症状，如头痛、耳鸣、恶心、颈痛和背痛。急性期通常表现为双侧葡萄膜炎和后葡萄膜炎，并且在此阶段会出现视力模糊，如果不及时治疗，视野、色觉和中央视力都可能会受到影响。恢复期发生于急性期后数周至数月，表现为由葡萄膜和/表皮色素减退。最后，在慢性复发期，可见轻度全葡萄膜炎并伴有前葡萄膜炎反复发作，这一阶段被认为是治疗不良或延迟的结果。

Revised diagnostic criteria (RDC) for human VKH have been proposed in 2001 to facilitate the dissemination of knowledge on the VKH disease and to support collaborative research efforts. These RDC divide the diagnosis of the VKH disease into three categories: complete, incomplete and probable. The first two categories are those needed to make a definitive diagnosis, whereas the probable VKH disease category, also referred to as “ocular VKH disease”, needs a continuous monitoring for the clinical signs that would confirm or refute the definitive diagnosis of this disease. Readers are referred to the article published by Read for more information on the clinical findings that determines the classification of human VKH disease into these three categories (Additional file 1: Table S1).

2001年制定了人VKH的诊断标准（RDC），以促进VKH疾病知识的传播，并鼓励合作研究的开展。RDC将VKH疾病的诊断分为三类：完全性、不完全性和可能性。前两个类别可以用来确诊，而可能性VKH也称为“眼型VKH”，需要持续监测临床症状，才能确诊。读者可参阅Read发表的文章，了解与VKH疾病三种分类相关的更多临床信息（附加文件1：表S1）。

Out of 134 dogs with a spontaneously-occurring UDS in which information on the location of the first sign/lesion (eye versus skin) was available, 114 (85%) developed ophthalmic clinical signs before the onset, or at least the recognition, of skin lesions. Eleven dogs (8%) had cutaneous lesions that preceded ophthalmic signs, whereas, in nine dogs (9%), the ophthalmic and dermatological lesions developed concurrently, or in an undetermined order. The location of the first sign/lesions were not stated in the remaining 34 dogs. The median and mean time-lapse between the ocular signs and skin lesions were 12 and 20 weeks, respectively (range: 4 days to 3 years); most dogs (18/21; 86%) that initially had either the eye or skin affected eventually had the two organs eventually bearing lesions within 6 months of each other. In one dog, however, bilateral uveitis developed 10 months after the onset of skin lesions.

在134只患有自发性UDS的犬中，发现了有关于原发症状/病变（眼睛vs皮肤）的位置信息，114只（85％）在发病前或至少在诊断皮肤病变时发现了眼部临床症状。11只（8％）犬在出现眼部症状之前出现皮肤病变，而在9只（9％）犬中，眼部和皮肤病变同时发生或不确定发生顺序。其余34只犬未给出原发病变部位。眼部症状和皮肤病变之间的中位时间间隔和平均时间间隔分别为12周和20周（范围：4天至3年）；大多数（18/21; 86％）出现原发眼部或皮肤病变的犬最终在6个月内两个器官发生病变。然而，有一只犬在皮肤病变发生10个月后才出现双侧葡萄膜炎。

In canine cases where this information was retrievable, the most common presenting ocular signs was blindness or poor/decreased vision (38/68; 56%). This is similar to what was reported by Zarfoss where 26/46 dogs (57%) had bilateral blindness at the initial presentation . Other commonly seen ocular signs were uveitis (27/68; 40%) and conjunctivitis or “red eye” (12/68; 18%); it is not known if the dogs with uveitis had concurrent conjunctivitis, and if the conjunctivitis was associated with the UDS or a separate cause.

在可获取该信息的犬病例中，最常见的眼部症状是失明或视力下降/萎缩（38/68；56％）。这与Zarfoss的报道类似，其中26/46只犬（57％）在初次发病时有双侧失明。其他常见的眼部症状是葡萄膜炎（27/68；40％）和结膜炎或“红眼”（12/68；18％）；目前尚不清楚患有葡萄膜炎的犬是否并发结膜炎，以及结膜炎是否与UDS或其他原因有关。

The most common skin lesions of canine UDS are leukoderma and/or leukotrichia, followed by erosions-ulcerations, alopecia, crust and erythema (Fig. 6). Other skin lesions reported have been a swelling of the nose, pruritus, hyperkeratosis of footpads and onychomadesis (loss of claws). It is interesting to note that the dog reported by Tachikawa developed onychomadesis 1 month after the initial onset of skin depigmentation, and ocular signs only developed 3 months after the first cutaneous lesions. In this dog, it is not known if the onychomadesis was associated with the UDS, was a separate disease (i.e., symmetric lupoid onychitis) that developed concurrently, or was a sequela to UDS due to antigen epitope spreading. Of note and to the authors’ knowledge, onychomadesis has not been reported in humans with the VKH disease.

犬UDS最常见的皮肤病变是白皮症和/或白毛症，其次是糜烂-溃疡、脱毛、结痂和红斑（图6）。其他皮肤病变包括鼻子肿胀、瘙痒、爪垫过度角化和脱甲病（爪脱落）。有趣的是，据Tachikawa报道，犬在最初出现皮肤色素减退的1个月后出现脱甲病， 3个月后出现眼部症状。在这只犬中，不知道脱甲病是否是与UDS相关，或仅是一种同时发生的单独疾病（如，对称性类狼疮样甲床炎），或由于抗原表位扩散而成为UDS的后遗症。值得注意的是，据作者所知，在患有VKH疾病的人中尚未报道过脱甲病。

Among 43 dogs in whom the distribution of skin lesions was reported, all (100%) exhibited lesions on the face or head (Fig. 6). The most common affected region on the face was the nasal planum (37/43; 86%), followed by the periorbital skin/ eyelids (32/43; 74%) and lips (28/43; 65%). Ten dogs (23%) had additional regions affected: the mouth/oral cavity, the footpads and/or the genitalia. Interestingly, all dogs (10/ 10; 100%) with genital (scrotum and/or prepuce) involvement were males. In the oral cavity, the most commonly affected region was the palate (4/10; 40%). In six dogs (14%), the lesions on the head/face progressed to generalized leukotrichia/ leukoderma. Depigmentation of the eyelashes was reported in six dogs (14%).

在报道了皮肤病变分布的43只犬中，所有（100％）犬都有面部或头部病变（图6）。面部最常见的病变部位是鼻平面（37/43；86％），其次是眶周皮肤/眼睑（32/43； 74％）和嘴唇（28/43；65％）。10只犬（23％）有其他病变区域：嘴/口腔、爪垫和/或生殖器。有趣的是，所有出现生殖器（阴囊和/或包皮）病变的犬（10/10； 100％）都是雄性。在口腔中，最常发生病变的区域是上颚（4/10；40％）。在6只犬（14％）中，头部/面部的病变发展为全身性白毛症/白皮症。6只犬（14％）发生睫毛色素减退。

Fig. 6 Canine uveodermatological syndrome. a chow-chow with bilateral uveitis and severe erosive dermatitis of the nasal planum, and philtrum (a), as well as lips and gingiva (b) (courtesy of Dr. E. Kuznetsova-Mendoza). c 8-year-old Siberian husky with periocular erythema, edema and erosions and, d acquired perioral vitiliginous depigmentation; this dog had uveitis 3 months before the cutaneous depigmentation (courtesy of L. Beco). e-f 2-year-old Akita inu with uveitis and mottled depigmentation, erythema, focal erosions and loss of the normal nasal planum architecture (courtesy of Dr. F. Banovic, case material NCSU)

图6 犬葡萄膜皮肤病综合征。一只患有双眼葡萄膜炎和严重的鼻平面及鼻中隔（a），以及嘴唇和牙龈（b）糜烂性皮炎的松狮犬。C.8岁的哈士奇患有眼周红斑、水肿和糜烂，d.可见嘴周的白斑状色素减退；这只犬在出现皮肤色素减退的3个月前患有葡萄膜炎。e-f.出现葡萄膜炎和点状色素减退、糜烂、面部水肿和鼻平面结构缺失的 2岁秋田犬。

In all reported cases, the ocular and skin lesions were bilateral and symmetrical except for one dog with iris heterochromia in which uveitis only developed in the right eye with the brown iris; the unaffected left eye had a blue-colored iris.

在所有报道的病例中，除了一只犬有虹膜异色症，其中葡萄膜炎仅出现在表现为棕色虹膜；正常的左眼有虹膜呈蓝色，其余眼睛和皮肤病变为双侧和对称的。

Concurrent systemic signs were reported in six dogs, shortly before, or at the time when, the diagnosis of UDS was made. The following systemic signs were reported: lethargy, a left head tilt with a change in behavior, lethargy and cranial nerve II deficit, dysacusis, left head tilt and reduced appetite, and transient pica and depression. In these dogs, the underlying cause of these signs was not determined and therefore, it is not known if they were part of the UDS symptomatology or a concurrent but unrelated finding. One dog was diagnosed with polymyositis 3 years after the onset of uveitis and glaucoma.

据报道，在确诊UDS前不久或确诊时，有6只犬并发全身症状。已报道的全身症状包括：嗜睡、左侧歪头伴行为改变、嗜睡和第II脑神经反射不良、听力减退、左侧歪头和食欲减退、一过性异食癖和精神沉郁。这些犬中，出现这些症状的根本病因尚未确定，因此，不知道它们是否是UDS症状学的一部分或仅是同时出现但与之无关。其中一只犬在出现葡萄膜炎和青光眼3年后被诊断患有多发性肌炎。

If the RDC for the VKH disease in humans were applied to all the dogs in this review, most would have been categorized as having either an incomplete or a probable VKH disease. However, it is important to realize that neurological and/or auditory signs in dogs may not be easily observed by the owner or confirmed when presented to the veterinarian, as signs such as meningismus (i.e., the presence of meningeal signs characterized by headache and neck stiffness without actual inflammation of the meninges) and tinnitus (i.e., perception of sound in the absence of external acoustic stimulus) are difficult to confirm or rule-out in dogs and/or these might have resolved by the time of examination. Tinnitus or auto-acoustic emission has been reported in dogs and can be classified as subjective (i.e., noise only heard by the patient) or objective (i.e., noise that can be heard by others). While the presence of objective tinnitus in dogs very much rely on an astute owner or veterinarian, a subjective tinnitus can neither be proven nor dismissed. Additionally, it is extremely difficult to clinically differentiate meningismus from overt meningitis or meningoenchephalomyelitis in animals [J. Rossmeisl, personal communication]. Nevertheless, there is one case report of a dog with the UDS in whom subclinical involvement of the meninges, based on post-mortem findings, has been documented.Importantly, this dog had not exhibited any clinical signs of meningismus when alive. As a result, the human RDC classification system appears to be of limited use for canine cases. Additionally, it is not clear if the four stages of human VKH disease can be applied to the canine UDS due to an absence of, or a failure to identify prodromal signs. However, most dogs with the UDS exhibit both ocular and dermatological signs, when or soon after being presented to the veterinarian, meaning that they are to be categorized in the convalescent stage.

如果将人VKH疾病的RDC应用于在本文中的所有犬，大多数将被诊断为具有不完全性或可能性的VKH疾病。但是，我们要认识到犬的神经系统和/或听觉症状可能不容易被主人和兽医观察到，如假性脑膜炎（如：出现头疼和颈部僵硬的脑膜炎症状，但没有急性脑膜炎症反应）和耳鸣（如：在没有外部声学刺激的情况下感觉到声音）难以在犬中确认或排除，和/或这些症状可能在检查时已经消失。在犬中已经有耳鸣或自发声的报道，并且可以归类为主观的（如：仅由患者听到的噪声）或客观的（即：其他人可以听到的噪声）。犬客观耳鸣的发现很大程度上要依赖于主人或兽医，主观耳鸣既不能被证实也无法被否定。此外，在动物中临床上区分假性脑膜炎与典型脑膜炎或脑膜脑脊髓炎是极其困难的。尽管如此，在一例患有UDS的犬病例报告中，根据验尸结果已经发现了脑膜的亚临床症状。重要的是，这只犬在生前没有表现出任何脑膜炎的临床症状。由此可知，人类RDC分类系统似乎在犬病例的应用中受限。此外，因为缺乏前兆，尚不清楚人VKH疾病的四个阶段是否可以应用于犬UDS。然而大多数患有UDS的犬在就诊前或之后很快就会出现眼部和皮肤病症状，这意味着他们将被归类为恢复期。

Three skin lesions listed in the RDC are alopecia, poliosis and vitiligo, and either one needs to be present to fulfill the criteria of human VKH with integumentary involvement. While vitiligo (leukoderma and/or leukotrichia) are the most common skin lesions of the canine UDS, the second most common ones are erosions and ulcerations. One possible reason why skin erosions and ulcers were not included (and therefore assumed to be very rare, if not nonexistent in the human VKH disease) might be due to an earlier diagnosis of this disease in humans, which results in an immediate and aggressive therapy that prevents the development of more advanced skin lesions such as painful erosions or ulcers.

RDC中列出的三个皮肤病变是脱发、白发病和白癜风，需要符合其中任一病症以满足人VKH的标准关于体外病变的要求。白癜风（白皮症和/或白毛症）是犬UDS最常见的皮肤病变，其次最常见的是糜烂和溃疡。RDC不包括皮肤糜烂和溃疡的一个可能原因（并且因此假设在人VKH疾病中非常罕见，如果不是不存在的话）是由于在人中该病的诊断位于疾病早期，及时和积极的治疗可以防止更多皮肤病变的发展，如疼痛的糜烂或溃疡。

Histopathology

组织病理学

Histologically, the canine UDS (Fig. 7a) is characterized by superficial perivascular inflammation that coalesces into a robust lichenoid pattern (i.e., a band-like below the epidermis) that includes macrophages, lymphocytes, plasma cells and a variable number of neutrophils. Macrophages are cited as a prominent feature but might not always be the dominant infiltrating cell type. The exocytosis of lymphocytes into the lower epidermis leads to a blurring of the dermo-epidermal junction, but basal keratinocyte injury and loss—a characteristic interface pattern—is limited or absent. There is partial-to-complete loss of melanocytes and, consequently, of epidermal pigmentation. The apoptosis of melanocytes is expected to occur but is rarely seen. Melanosomes (melanin granules) are spilled to the dermis and are found in melanophages (pigmentary incontinence) were they appear as a finely granular, dusted, cytoplasmic pigment (Fig. 7b). These fine granules have been cited to be a characteristic feature of this disease but the sensitivity and specificity of such microscopic lesion for the diagnosis of the canine UDS has not been proven. Coarsely-clumped pigment can also accompany fine pigment melanophagia. The dermal inflammation pattern is sometimes nodular and periadnexal, but it can be sparse in advanced disease stages. An epidermal hyperplasia is normally seen and can be accompanied by erosions, ulcers, neutrophil transmigration, patchy parakeratosis and/ or crust formation. Skin biopsies are indispensible to confirm the diagnosis and should be performed early in suspect cases because of the need to treat early in order to reduce the possibly of blindness. Multiple skin biopsies should be collected from the margins or lesions in areas of recent depigmentation, especially those with active inflammation that exhibit erythema and swelling, which can be subtle.

在组织学上，犬UDS（图7a）的特征为浅表血管周围炎性浸润，形成紧实的苔藓样结构（如，表皮下的带状组织），包括巨噬细胞、淋巴细胞、浆细胞和数量不等的中性粒细胞。巨噬细胞被认为是其特征性表现，但可能并不总是主要的浸润细胞类型。淋巴细胞深入表皮下部导致表皮-真皮交界处结构不清，但基底角质形成细胞损伤和丧失-特征界面模式-受限或消失。黑色素细胞部分至完全丧失，因此表皮色素减退。黑色素细胞的凋亡很少见到。色素小体（色素颗粒）漏出到真皮中，并且在噬黑素细胞（色素失禁）中发现，它们看起来是细颗粒状，粉尘状的细胞质色素（图7b）。这些细颗粒被认为是该疾病一个特征标志，但这种微观病变对犬UDS诊断的敏感性和特异性尚未得到证实。粗糙块状的色素也可以伴随微小色素的色素失禁。皮肤炎症有时是结节性，存在附件周围，但在疾病发展阶段可能是稀疏分布。通常可见表皮增生，并且可伴有糜烂、溃疡、中性粒细胞迁移、散在的角化不全和/或结痂形成。皮肤活检对于确诊是必不可少的，且在可疑病例中应尽早进行，因为尽早治疗可以尽量避免失明。应从最近发生色素减退的区域边缘或病变处进行多处采样活检，尤其是出现红斑和肿胀的炎症区域。

Fig. 7 Histopathology of canine uveodermatological syndrome. Skin biopsy from the face of a dog. a just below a partially depigmented epidermis, a band-like (lichenoid) dermal infiltrate is dominated by macrophages and lymphocytes with fewer plasma cells and neutrophils. Hematoxylin and eosin. 200X. b inset from image (a) above: lymphocytes (arrow heads) infiltrate the deep epidermis in low numbers and occasionally appear to surround melanocytes (i.e., “satellitosis”). Melanosomes are spilled into the dermis, where they appear as a fine granular, dust-like, appearance in macrophages (arrows). Hematoxylin and eosin. 400X

图7 犬葡萄膜皮肤病综合征组织病理学。犬面部皮肤活检。在局部色素减退的表皮层下，大量巨噬细胞和淋巴细胞，以及少量浆细胞和中性粒细胞在真皮浸润，形成带状（苔藓样变）。HE染色，200倍。b 上图的局部放大：表皮深层可见少量淋巴细胞（箭头）浸润，偶尔可见周围着黑色素细胞（如“卫星现象”）。色素小体漏出至真皮层，表现为细颗粒、尘土样，出现在巨噬细胞中（箭头）。HE染色，400 倍

Treatment and outcome

治疗和效果

The early and high-dose administration of oral GCs is the mainstay of the VKH disease therapy in humans. Studies have shown that the treatment with high-dose GCs within 2 weeks of disease onset resulted in a shorter duration of steroid use, a higher chances of obtaining a complete remission and a shorter duration of disease. The length of systemic GC treatment should also be at least 6 months to reduce the risk of recurrence and severe vision loss, but there are no guidelines on the most effective tapering regimen. For patients with a chronic and recurrent disease, or for those who are intolerant to systemic GCs, immunosuppressive agents such as ciclosporin, azathioprine, methotrexate, chlorambucil, mycophenolate mofetil and cyclophosphamide can be used. Whether or not an adjunctive immunosuppressive agents should be employed as a first-line therapy remains a topic of discussion among VKH experts; results of several uncontrolled studies have suggested, however, that an initial multimodal immunosuppressive therapy resulted in a better visual outcome and control of inflammation compared to a monotherapy with GCs alone. Finally, topical GC and cycloplegic agents are indicated to reduce inflammation and pain and to prevent the appearance of synechiae (adhesions). The former can be administered either as ophthalmic drops, intravitreal or subtenon injections. In the human VKH disease, parameters such as the fine visual acuity, the development of cataract, glaucoma or pigmentary changes in the fundus are often used for the assessment on the effectiveness of a treatment protocol. However, there is no agreement on a set of clinical outcomes that would define a patient’s VKH disease as being in clinical remission (CR) or having had a treatment failure.

尽早地口服高剂量GCs是人类治疗VKH的主要治疗方案。研究表明，在疾病发作后2周内接受高剂量GCs治疗可以缩短类固醇的持续使用时间，疾病痊愈的机会更大，病程也更短。全身GC的治疗时间至少为6个月，以降低复发和严重视力丧失的风险，但并没有关于如何最有效的逐步减量的方案指南。对于患有慢性和复发性疾病的患者，或对全身GCs不耐受的患者，可以使用免疫抑制剂如环孢素、硫唑嘌呤、氨甲蝶呤、苯丁酸氮芥、霉酚酸酯和环磷酰胺。是否应将辅助免疫抑制剂用作一线治疗方案仍是VKH专家讨论的热门话题；然而，几项无对照研究结果表明，与单独使用GC进行治疗相比，最初就选择多种免疫抑制药物联合用药其视力的预后和炎症控制更好。最后，外部GC和睫状肌麻痹剂可用于减轻炎症和疼痛，并防止粘连（粘连）的发生。前者可以通过眼滴眼液、玻璃体内注射或眼筋膜囊注射给药。在人VKH疾病中，诸如视力评估、白内障、青光眼或眼底色素变化等参数通常用于评估治疗方案的有效性。然而，对于如何将VKH疾病根据临床效果定义为临床症状缓解（CR）或治疗失败尚未达成一致。

Similarly, there is no consensus on the definition of CR for the canine UDS, which is largely due to the heterogeneity and lack of standardization of case reports.For the purpose of this review, we will define CR as either one of the following:

1. an improvement or the re-establishment of vision in dogs presented with blindness, or,

2. an absence of development of new signs, or,

3. a lack of progression of lesions (ocular and skin) with resolution of existing ones.

同样，由于病例报告的不均一性，并缺乏标准，关于犬UDS的临床恢复的定义并没有达成统一。

在本文中，我们将CR定义为以下几种情况：

1.失明犬的视力改善或恢复，或，

2.无新症状的出现，或，

3.病变（眼睛和皮肤）未发展，现有病变消退。

A “failure of therapy” is defined as an inability to control the disease activity (i.e., a continuous development of new ocular signs or skin lesions, a progression/extension of old lesions, or a lack of improvement of ocular signs and/or skin lesions).

“治疗失败”被定义为无法控制疾病的发展（如：不断出现新的眼部病变和皮肤病变，旧病变的发展/扩大，或眼部症状和/或皮肤病变未见改善）。

Altogether, detailed information about the treatment and outcome of the canine UDS can be inferred from 29 reports including 47 dogs. Another six dogs were either not treated, lost to follow-up or the information on the final outcome was incomplete.

总之，可以从29篇报告中总结出有关犬UDS治疗和其结果的详细信息，其中涉及47只犬。另外六只犬要么没有治疗，要么没有随访，或者最终有关治疗效果的信息不完整。

Overall, the CR of UDS was obtained in 29/47 dogs (62%). The time-to-CR varied between 2 weeks to 10 months. A spontaneous remission of the UDS has not been reported so far. In dogs for whom follow-up information was available, eight experienced a relapse: clinical signs flared in five dogs when oral GCs were tapered and in three dogs, 3–5 months after treatment was stopped.

总体而言，UDS的CR达到29/47只犬（62％）。CR的时间在2周到10个月不等。到目前为止，尚未有UDS自愈的报道。在有随访信息的犬中，有8例复发：当口服GCs剂量逐渐减少时，5只犬出现临床症状，3只犬在治疗停止3-5个月后复发。

Treatment regimens have varied widely, and they included the following: GCs (oral, topical ophthalmic and/or subconjunctival), calcineurin inhibitors (ciclosporin or tacrolimus), azathioprine, cyclophosphamide, chlorambucil and mycophenolate mofetil. At the time when a CR was documented, 28/29 (97%) of dogs were treated with oral GCs, of which 18 were concurrently receiving topical ophthalmic, subconjunctival GC or topical ophthalmic calcineurin inhibitors; seven dogs (25%) were concurrently treated with azathioprine. Oral GC monotherapy resulted in a CR of signs in only 3/28 dogs (11%). In most dogs receiving oral GCs, the minimum dosage was 2 mg/kg/day with the dosage slightly lower (1-2mg/kg/day) in dogs treated concurrently with other immunosuppressants. Interestingly, of 18 dogs (38%) in which a disease CR was not achieved (failure of therapy), oral GCs with or without other immunosuppressant were used as treatment in 15 (83%). The treatment regimen was not stated in one dog that had both eyes enucleated.

治疗方案间的差异很大，其中包括：GCs（口服、眼部和/或结膜下外部给药）、钙调神经磷酸酶抑制剂（环孢素或他克莫司）、硫唑嘌呤、环磷酰胺、苯丁酸氮芥和霉酚酸酯。在临床恢复时，28/29（97％）的犬使用口服GCs治疗，其中18只同时接受眼部、结膜下GC外部给药，或眼部外用神经钙蛋白抑制剂；七只犬（25％）同时服用硫唑嘌呤。口服GC单一疗法仅有3/28只犬（11％）出现CR。在接受口服GC治疗的大多数犬中，最小剂量为2mg / kg /天，联合其他免疫抑制剂治疗的犬的剂量略低（1-2mg / kg /天）。有趣的是，在未出现CR的18只犬（38％）中（治疗失败），15只（83％）犬接受口服GCs，联用或不联用其他免疫抑制剂。一只双眼眼球摘除的犬未给出其治疗方案。

There is no single treatment protocol that appeared to be associated with the obtention of a more rapid disease CR or a higher treatment success or failure rate. There are 19 case reports where information on the final treatment outcome and time lapsed between the initial onset of signs and the initiation of treatment after the diagnosis of UDS were available – a total of 29 dogs. Of these, 12/20 (60%) and 4/20 dogs (20%) in which CR was achieved, had been treated 1 month and 2–6months after the onset of clinical signs, respectively. This observation implies that initiating treatment within 1 month after the first clinical signs would result in a better outcome. This is supported by the outcome of 8/9 dogs (89%) in which treatment failed to induce CR that had been treated within 6 months of sign development. This observation is in contrast with the results obtained by Zarfoss et al. who reported that any use of immunosuppressive drugs, duration of signs prior to treatment and high daily doses of GC and azathioprine was not significantly associated with a better prognosis.

没有哪一种单一的治疗方案与更快达到临床症状缓解或更高的治愈率或失败率有关。这里有19例病例报告，其中记录了有关最终治疗效果的信息及最初发病与诊断UDS后首次治疗之间的时间间隔，共29只犬。其中，出现CR的12/20（60％）和4/20只犬（20％）分别在出现临床症状后1个月和2-6个月进行治疗。这一观察结果表明，在首次出现临床症状后1个月内开始治疗的效果更好。临床症状发展6个月内进行治疗，结果8/9只犬未出现CR，该结果支持了这个结论。该观察结果与Zarfoss等人的研究结果形成对比，据他们报道任何免疫抑制药物的使用，治疗前临床症状的持续时间，每日高剂量服用GC和硫唑嘌呤都与获得更好的预后无明显关联。

Implications for practice

临床意义

Similarly to the human VKH disease, the diagnosis of the canine UDS needs to be made in the shortest time possible, thus allowing for the implementation of an immediate immunosuppressive treatment to prevent disease progression and the development of ocular complications, especially blindness. Because ocular lesions are the most common presenting sign in canine UDS, veterinarians should be extremely vigilant when presented with dogs with non-traumatic or non-infectious signs of conjunctivitis or uveitis, especially in predisposed breeds such as the Akita, Siberian Husky and Samoyed. A complete ophthalmological examination should be performed, and whenever faced with any doubt, the prompt referral to a veterinary ophthalmologist is recommended. On the other hand, dogs presented with only dermatological signs in which histopathology is consistent with a canine UDS, should also undergo a complete ophthalmological examination and continued ophthalmic monitoring even if ocular signs were not reported or if skin lesions were to respond to treatment.

与人VKH疾病类似，需要尽快确诊犬UDS，以尽早进行免疫抑制治疗来预防疾病的发展和眼部并发症，尤其是失明的发生。由于眼部病变是犬UDS中最常见的症状，因此兽医在发现具有非创伤性或非感染性结膜炎或葡萄膜炎症状的犬时应特别警惕，特别是易感品种如秋田、哈士奇和萨摩。应对其进行全面的眼科检查，如有任何疑问，建议立即转诊兽医眼科医生。另一方面，仅出现皮肤病变的犬如果其组织病理学与犬UDS一致，即使未发现眼部病变或治疗对皮肤病变有效，也应进行全年的眼科检查和持续的眼科监测。

Topical ophthalmic together with systemic GC should be the first-line therapy for the canine UDS, with the dose of oral GC started at 2 mg/kg/day or higher. Other immunosuppressive therapies, such as azathioprine or ciclosporin, should be added into the treatment regimen should GC therapy fail to induce the CR of signs.

全身性GC用药结合眼部GC用药是犬UDS的一线治疗方案，口服GC的起始剂量为2mg / kg /天或更高。如果GC治疗不能达到CR，则应在治疗方案中加入其他免疫抑制疗法，如硫唑嘌呤或环孢素。

Implications for research

研究意义

Specific diagnostic criteria need to be established for the canine UDS. This requires the collaboration of veterinary ophthalmologists, dermatologists and neurologists.The presence or absence of neurological and/or auditory abnormalities in the canine UDS should be investigated further via ancillary test such spinal taps to determine if pleocytosis of the cerebrospinal fluid is present in dogs with this disease. Likewise, diagnostic tests that are more sensitive and can reliably detect tinnitus in dogs should be investigated. The ability to detect prodromal signs (if present) in dogs with the UDS would likely result in a better prognosis because treatment could be started sooner.

犬UDS需要建立特定的诊断标准。这需要兽医眼科医生、皮肤科医生和神经科医生的共同合作。 犬UDS中是否存在神经和/或听觉异常应通过辅助检查进行进一步研究，例如脊髓穿刺，以确定该病患犬是否存在脑脊液的细胞增多症。同样，应探索更为敏感且可靠的诊断手段已进行犬耳鸣的检测。如果可以识别UDS犬的前驱症状（如果存在）就可以更早开展治疗，也会得到更好的预后结果。

A validated scoring system or index for treatment response would be of value, as it would allow for a standardization of the reporting of treatment outcomes among publications, thus allowing for a better assessment and comparison of treatment efficacy. This, in turn, would facilitate the establishment of guidelines for the treatment and management of the canine UDS. With this, the usage of biologic agents with minimal adverse effects could then be explored as the future treatment for canine UDS.

经过验证的用于治疗效果的评分系统或指数将是有价值的，因为它将使已报道的治疗结果报告标准化，从而更好地评估和比较治疗效果。反过来，这也将有助于制定犬UDS的治疗和管理指南。通过这种方式，可以探索使用具有最小副作用的生物制剂作为犬UDS的未来治疗方法。

Conclusions

结论

Autoimmune diseases targeting melanocytes can manifest with a wide range of clinical signs. It remains a mystery as to why “attacks” on the same pigmented cells, the melanocytes, results in just depigmentation of the skin in some dogs or leads to a “catastrophic” effect on the eyes and/or skin in others. Until the exact etiology is known, the treatment of canine vitiligo should take into consideration the efficacy (or lack of ) of a particular therapy and weigh the adverse effects of treatment for this mostly cosmetic disease. On the other hand, the prompt implementation of an aggressive immunosuppression cannot be overemphasized for the treatment of canine UDS to prevent blindness in affected patients.

以黑色素细胞为目标的自体免疫疾病可以表现出多样的临床症状。关于为什么攻击相同的色素细胞，即黑色素细胞，会导致某些犬的皮肤色素减退，或导致其他犬的眼睛和/或皮肤出现“灾难性”影响仍然是一个谜。在明确病因学之前，犬白癜风的治疗应考虑到特定疗法的有效性（或无效），并权衡对这种主要影响美观的疾病的治疗副作用。另一方面，在治疗犬UDS中，为了预防患病动物失明的风险，对于有侵袭性的免疫抑制疗法不能过激使用。

zhangenzyme

Ryohei

秘鸢

南海

锦寒

青春年少