犬皮肤红斑狼疮—变异型新发现

王帆

犬皮肤红斑狼疮—变异型新发现

Canine  Cutaneous  Lupus Erythematosus

Newly  Discovered Variants

作者：Frane Banovic, DVM, PhD

翻译：侯宁  校对：王帆

关键词

•自体免疫性皮肤病•红斑狼疮•皮肤•犬•皮肤病学

KEYWORDS

•Autoimmune skin disease •Lupus •Skin •Canine •Dermatology

重点

·犬皮肤红斑狼疮（CLE）变异种类很多。

·犬盘状红斑狼疮（GDLE）通常表现形式为，颈部下方的红斑样盘状斑块，伴有粘附性皮屑和色素减退。

·黏膜红斑狼疮（MCLE）中，最常于犬肛门和肛周，或生殖器和生殖器周围的红斑性糜烂和溃疡。

·在发表的犬MCLE病例中，德国牧羊犬及其杂交品种大约占了一半。

·犬GDLE和MCLE似乎对许多治疗方法都有效，但大多数病例在逐渐降低药物剂量后会复发。

KEYPOINTS

·Canine cutaneous lupus erythematosus (CLE) variants are heterogeneous.

·In the generalized form of discoid lupus erythematosus (GDLE) in dogs, erythematous disc-like plaques with adherent scaling and dyspigmentation occur below the neck.

·In mucocutaneous lupus erythematosus (MCLE), erythematous erosions and ulcers affect most commonly anal/perianal regions or genital/perigenital areas in dogs.

·German shepherd dogs and their crosses represent approximately half of the dogs in published MCLE cases.

·Canine GDLE and MCLE seem to respond to a wide range of treatments, but a majority of the cases experience relapse on the tapering of drug dosages.

介绍

INTRODUCTION

在人医中，使用Sontheimer-Gilliam分类法，将红斑狼疮（LE）出现的皮肤病变进行分类，分为显微镜下以富含淋巴细胞的界面性皮炎为特征伴有基底膜角质细胞损伤，（如：特异性狼疮皮肤病=皮肤型LE（CLE））和没有这些显微模式的疾病（如：非特异性LE皮肤病）。特异性红斑狼疮皮肤病可细分为急性CLE、亚急性CLE和慢性CLE（CCLE）。这些命名是根据单个病例皮肤病变形态和平均持续时间来划分的。在几种人CCLE变异型中（如：盘状红斑狼疮（DLE）、疣状LE（角化过度）、冻疮样LE、肿胀性红斑狼疮和深部狼疮），DLE是最常见的形式。

In humans, the Sontheimer-Gilliam classification divides the skin lesions that can be encountered in lupus erythematosus (LE) into those with characteristic microscopic changes of lymphocyte-rich interface dermatitis with basal keratinocyte damage (ie, lupus-specific skin diseases = cutaneous LE [CLE]) and those without such microscopic pattern (ie, LE-nonspecific skin diseases). The LE-specific skin diseases are subdivided into acute CLE, subacute CLE, and chronic CLE (CCLE) types; these designations refer to both the lesional morphology and the average duration of individual skin lesions. Among the several variants of human CCLE (eg, discoid LE [DLE], verrucous (hyperkeratotic) LE, chilblain LE, lupus tumidus, and lupus profundus), DLE represents the most common form.

1979年，Griffin和同事报道了2例以局部鼻部皮炎为主的犬，诊断为与人DLE相似疾病。在随后的40年里，通过几个病例分析，犬CLE变异型出现了新的描述。最近，参考人CLE疾病，提出了一项新的犬CLE分类方法（图1）。

In 1979, Griffin and colleagues reported 2 dogs with localized nasal-predominant dermatitis diagnosed as affected with the canine counterpart of human DLE. Within the ensuing 4 decades, novel descriptions of canine CLE variants occurred through several case series.  Recently, a proposal of the novel CLE classification in dogs (Fig. 1), derived from the corresponding human CLE diseases, has been published.

本综述中，作者报道了最近两个CLE变异型病例的病史和临床表现，GDLE和皮肤黏膜LE（MCLE），最后，综述这两种疾病目前的推荐治疗方法。

In this review, the author presents the historical and clinical features characteristic of 2 recently described CLE variants, GDLE and mucocutaneous LE (MCLE) and, finally, a review of current treatment recommendations for these variants.

全身性盘状红斑狼疮

GENERALIZEDDISCOIDLUPUSERYTHEMATOSUS

病史调查和临床症状

Historical andClinicalFinding

自首次将犬的鼻部皮炎为主的病变描述为与人DLE类似的疾病以来，随后2份大型病例分析报道了犬局灶性DLE的出现经典面部（鼻部）平面为主的病变（图2A）。这导致人们普遍认为犬DLE即为鼻平面的局灶病变。在人医中，局灶型DLE和GDLE间存在差别，局灶型DLE的皮肤病变局限于头部和颈部，GDLE的皮肤病变通常发生于颈部以下，伴有或不伴有头部病变。最近，在犬中发现了一种与人全身性DLE类似的广泛分布的表现型。

Since the first description of nasal-predominant dermatitis as the canine counterpart of  human DLE, 2 large case series of  dogs  with  classic  facial  (nasal) planum-predominant localized DLE followed (Fig. 2A).  This resulted in the widespread acceptance of canine DLE equated mainly with localized lesions affecting nasal planum. In humans, a distinction between localized DLE, where skin lesions are confined to the head and neck, and the GDLE (GDLE) form, in which skin lesions occur below the neck with or without involvement of the head, exists. Recently, a widespread phenotype that resembled that of the generalized variant of human DLE has been described in dogs.

犬GDLE主要为成年犬发病。在最近的10例犬的病例分析中，GDLE皮肤病变的发病年龄从5岁到12岁，中位年龄为9岁。母犬/公犬比例为1.0。所有犬都已绝育。不同种类的犬都可患GDLE（如：中国冠毛犬、拉布拉多犬、迷你杜宾犬、兰波格犬、西施犬和玩具贵宾犬）。德国牧羊犬及其杂交品种，易患面部（鼻部）平面为主的局灶DLE，未患GDLE。

Canine GDLE typically affects adult dogs. In a recent case series of 10 dogs, the age of onset of GDLE skin lesions ranged from 5 years to 12 years, with a median age of 9 years. The female/male ratio was 1.0; all dogs were castrated. Different breeds were affected by GDLE (ie, Chinese crested dogs, Labrador retrievers, miniature pinscher, Leonberger, shih tzu, and toy poodle).German shepherd dogs and their crosses, which are predisposed to develop facial (nasal) planum-predominant localized DLE, were not affected by GDLE.

GDLE的主要病变是伴色素改变（色素减退和色素沉着）的环状（盘状）至多环状斑块，边缘红斑，粘附性皮屑，毛囊管型和中央脱毛（图2B，C）。表现为典型的全身性或多灶性病变，分布在颈部、背部、胸侧和 胸腹；在一些犬中，病变延伸至黏膜皮肤交界处。临床上病变会进一步发展；在一些犬会表现出不常见的弥散性色素沉着，而在其他犬中出现伴有色素减退或色素沉着的中央萎缩性或增生性瘢痕（图2D-F）。

The primary lesions in GDLE are annular (discoid) to polycyclic plaques with dyspigmentation (depigmentation and hyperpigmentation), an erythematous margin, adherent scaling, follicular plugging, and central alopecia (Fig.  2B, C). The lesions are typically generalized or multifocal and distributed over the neck, dorsum, and lateral and ventral thorax; in some dogs, mucocutaneous junctions are affected. Lesions can advance at clinical presentation; some dogs develop an unusual pattern of diffuse reticulated (netlike) hyperpigmentation whereas in other dogs central atrophic or hypertrophic scars with depigmentation or hyperpigmentation occur (Fig. 2D–F).

与GDLE临床症状相似的皮肤病有过度角化的多形红斑和全身性缺血性皮肤病。

The main dermatoses with clinical signs mimicking GDLE are hyperkeratotic erythema multiforme and generalized ischemic dermatopathies.

图1.VCLE，ECLE，局部（面部）DLE或GDLE和MCLE是目前公认的犬CLE亚型。

Fig. 1. VCLE, ECLE, localized  (facial) DLE or GDLE, and MCLE are the currently  recognized subtypes of canine CLE.

图2.犬面部和GDLE的临床表现。（A）一只德国牧羊犬面部DLE，鼻部病变表现为红斑、色素减退、溃疡和结痂；可见鹅卵石外观消失。（B-D）GDLE患犬胸廓皮肤的盘状、环形和多环形斑块，伴有色素沉着、局灶色素减退和瘢痕；边缘有局灶性溃疡。（E）腹侧一处不常见的网格状（网状）色素沉着，伴有脱毛。（F）环形色素沉着斑点和斑片，中央组织结构丧失，并附着有明显的银色皮屑，周围边缘伴有红斑和局灶性溃疡。

Fig. 2. Clinical characteristics of canine facial and GDLE. (A) Erythematous, depigmented, ulcerated, and crusted nasal lesions of facial DLE in a German shepherd dog; complete loss of cobblestone  appearance is visible. (B–D) Disc-shaped, annular,  and polycyclic plaques with hyperpigmentation, focal depigmentation, and scarring on the thorax  of dogs with  GDLE; focal ulcers at margins are present. (E) An unusual pattern of reticulated (netlike)  hyperpigmentation with  alopecia on the ventral abdomen. (F) Hyperpigmented annular macules and patches with  central  loss of  tissue architecture and prominent silver adherent  scales surrounded  by a peripheral erythematous  margin  and focal ulceration.

实验室检查、组织病理学和免疫学评估

Laboratory,Histopathology,andImmunologicEvaluation

目前诊断犬GDLE没有特异性常规实验室检查方法。一些人GDLE患者在被诊断出皮肤病的5年中有患全身性红斑狼疮（SLE）的风险。临床中仅发现1只GDLE患犬发展为SLE。虽然在大多数GDLE患犬中没有临床症状证明存在内科病，但也应该进行进一步的检查，如全血细胞计数、血液生化和尿液分析以排除SLE。人SLE患者抗核抗体（ANAs）滴度较高；ANAs是抗核成分的自身抗体，包括单链和双链DNA。所以，所有诊断为SLE的犬需要通过血清ANA检测来排除并发SLE。虽然在最近的GDLE病例中，1:40的血清稀释液偶见ANA检测阳性，但可以通过缺乏全身症状，实验室检查未见肾脏和血液学异常来排除SLE。

There are no specific routine laboratory findings in canine GDLE. Some human GDLE patients are at risk for development of systemic LE (SLE) within 5 years after the initial diagnosis of skin lesions.The progression to a clinical SLE was observed in only 1 GDLE dog.  Despite no clinical signs justifying internal involvement in most GDLE dogs, further investigations, such as complete blood cell count, serum chemistry profile and urinalysis, are performed to rule out concurrent SLE. Human SLE patients have high titers of circulating antinuclear antibodies (ANAs); ANAs are autoantibodies against nuclear components,  including double-stranded  and single-stranded DNA and histones.Therefore, to rule out coexisting SLE, the ANA serology should be evaluated in all dogs diagnosed with GDLE. Although the ANA serology was occasionally positive at a 1:40 serum dilution in the recent GDLE case series, based on the lack of systemic signs and negative laboratory results suggesting renal or hematologic involvement, a diagnosis of coexisting SLE was ruled out in all dogs.

犬GDLE的诊断是根据病史调查和临床症状，并辅以典型的组织病理学的支持。皮肤活检需要选取患病动物的多处病健交界处皮肤。犬GDLE的组织学检查表现为大量淋巴细胞浸润的界面性皮炎和毛囊炎（图3A-C）。在疤痕的慢性病变中，真皮浅层炎性细胞浸润偶尔被真皮纤维所取代。

Diagnosis of canine GDLE is based on history and clinical presentation supported by characteristic histopathologic findings. Multiple skin biopsies should be collected from affected dogs at the areas of active margin to normal skin. The histology of GDLE in dogs is characterized by a cell-rich, lymphocytic interface dermatitis and folliculitis (Fig. 3A–C). In chronic lesions with scarring, dermal fibrosis occasionally displaces the cell-rich inflammatory infiltrate from the superficial dermis.

采用直接免疫荧光法，可以在90%GDLE患犬的表皮真皮连接处检测到免疫球蛋白的沉淀（图3D）；这种沉淀类似于人CLE中的狼疮带检测。大多数犬在皮肤病变处可见表皮真皮结合处的基底膜区IgG和IgM的线状沉淀，这与人DLE的病变类似。

Using a direct immunofluorescence method, immunoglobulin deposition at the dermoepidermal junction could be demonstrated in 90% of dogs with GDLE (Fig. 3D); the deposition resembles the lupus-band test observed in humans with CLE variants. A majority of dogs exhibited a linear deposition of IgG and IgM antibodies at the dermoepidermal basement membrane zone of lesional skin, which is similar to what is seen in human DLE lesions.

图3.GDLE的组织病理学。（A）躯干部皮肤的活检，表现大量淋巴细胞浸润的界面性皮炎（H&E染色，放大倍数×40）。（B,C）淋巴细胞浸润表皮基底层，与基底细胞空泡样细胞凋亡，和组织损伤开裂有关（H&E染色，放大倍数×40）。（D）沿着表皮基底膜区可见连续的线性IgG沉淀（如狼疮带检测阳性）。IgG沉淀通过免疫荧光放大呈现，真皮浅层发出荧光的圆形细胞代表IgG阳性血浆细胞，是炎性表皮真皮结合处的常见现象（二氨基苯吲哚染色法（DAPI）进行抗IgG的染色，×109）。

Fig. 3. Histopathology of GDLE. (A) In a skin biopsy from  the trunk,  a cell-rich lymphocytic interface  dermatitis is present (H&E, original magnification x40). (B, C) Lymphocytes infiltrate the basal layer of epidermis and are associated with  basal cell vacuolation, apoptosis, loss, and disorganization at the cleft margin (H&E, original magnification x40). (D) Continuous and linear IgG deposition along the epidermal  basement membrane zone (ie, positive lupus band test). Magnification of IgG deposition with  fluorescent  round cells in the superficial dermis that  represent IgG-positive plasma cells, a common finding at inflamed mucocutaneous  junctions  (Anti-IgG  fluorescein  with  diamidino phenylindole (DAPI) stain, 109 magnification).

皮肤黏膜红斑狼疮

MUCOCUTANEOUS LUPUSERYTHEMATOSUS

组织学和临床检查发现

Historical andClinicalFindings

    在20世纪90年代中叶， 首次报道2例德国牧羊犬以生殖器病变为主的DLE。表现为生殖器周围糜烂性皮肤病。正如之前描述的，靠近粘膜处的慢性糜烂和溃疡性病变并不是GDLE的典型特点，且面部的DLE主要侵犯鼻面。1998年，Olivry提出诊断术语，皮肤粘膜LE（MCLE）是指，以粘膜周围溃疡病变为主要特征，伴有CLE的典型微观病理改变。(Olivry T: British 兽医皮肤病研究小组, York (United Kingdom),1998)。不幸的是，在过去20年中这种关于犬的皮肤粘膜疾病的术语一直在变化。与之相似的粘膜周围的糜烂性表现型被称为DLE或肛周/外阴周围的LE。2015年，Olivry和其同事把21只患有糜烂性皮肤粘膜糜烂病变的犬的病史、临床表现和组织学特点，与CLE的组织病理学特点相比较。通过这些病例制定了MCLE的诊断方法，并将其作为犬CCLE的另一种分型。

In the mid-1990s, an erosive skin disease affecting perigenital areas in 2 German shepherd dogs was first reported as a genital-predominant DLE. As described previously, chronic juxtamucosal erosive and ulcerative lesions are not a feature of GDLE and facial localized DLE predominantly affects the nasal planum. In 1998, Olivry proposed the diagnosis term, mucocutaneous LE [MCLE], for the canine disease characterized by perimucosal ulcerative lesions areas with a microscopic pathology typical of CLE (Olivry T: British Veterinary Dermatology Study Group, York (United Kingdom),1998). Unfortunately, the terminology of this canine mucocutaneous disease continued to vary in the past 2 decades; additional cases of similar perimucosal erosive phenotype were published as DLE or perianal/perivulvar LE. In 2015, Olivry and colleagues compared the historical, clinical, and histologic features of 21 dogs affected by erosive mucocutaneous erosions and a CLE histopathology; the MCLE diagnosis was coined for these cases and proposed as another variant of canine CCLE.

MCLE是一种罕见疾病，各种品种成年犬患病；德国牧羊犬及其杂交品种占所有报道的犬MCLE病例一半以上。据报道，德国牧羊犬易患SLE和典型面部局灶性DLE。在21只犬病例分析中，MCLE皮肤病变的发病年龄差异较大，从3岁到13岁不等（平均6岁）。雌性与雄性的比例为1.8。如果将已报道患病的德国牧羊犬/比利时牧羊犬及其杂交品种，雌性犬数量将是现有报道的四倍。

MCLE is a rare disease that affects adult dogs of various breeds; German shepherd dogs and their crosses represent approximately half of all published cases of canine MCLE. German shepherd dogs are reported to be predisposed to develop SLE and facial localized classic DLE. In a case series of 21 dogs, the age of onset of MCLE skin lesions varied widely and ranged from 3 years to 13 years (median; 6 years).  The female-to-male  ratio  was 1.8; if only all published  data affecting German/Belgian shepherds and their crosses are included, female dogs appear approximately 4 times over-represented.

主人发现MCLE动物在大便(大便困难)和/或小便（小便困难）时，皮肤粘膜疼痛，是个有意思的特征。 MCLE的典型病变是边界清晰的多灶至补丁状分布的红斑性糜烂和溃疡（图4）；大多数病例出现全身性病变并会继发结痂。色素的改变，如色素沉着，常出现在溃疡性病变周围或在之前病变部位。

One interesting feature of MCLE is that the owners report mucocutaneous sores and pain that manifests while defecating (dyschezia) and/or urinating (dysuria). The characteristic lesions of MCLE are well-demarcated multifocal to patchy erythematous erosions and ulcers (Fig. 4); most cases have symmetric lesions and in some secondary crusting develops. Pigmentary changes, such as hyperpigmentation, often surround ulcerative lesions or develop at the site of previous lesions.

MCLE的粘膜病变最常发生于肛门/肛周区域（见图4A）或生殖器/生殖器周围（见图4B，C）；极少数病例中病变发生于唇周（见图4D），眼周，和鼻面。通常兽医在看诊时，在大多数犬可以观察到2个或以上的粘膜周围区域或粘膜区域。绝大多数犬除了大小便时的痛感外未见其他全身症状。

The mucocutaneous lesions of MCLE most commonly occur on the anal/perianal regions (see Fig. 4A) or genital/perigenital (see Fig. 4B, C); in rare cases, lesions have been noted around the lips (see Fig. 4D), eyes, and nasal planum. At the time of presentation to the veterinarian, a majority of dogs had 2 or more perimucosal or mucocutaneous regions involved. There were no systemic signs observed outside of pain when defecating and urinating or at the site of lesions in the majority of dogs.

与MCLE病变类似的鉴别诊断包括粘膜性脓皮病（MCP）和粘膜性类天疱疮（MMP）。MCP是犬的一种缺乏典型特点的皮肤病，极易感染鼻面或口周皮肤，是一种糜烂少结痂多的类型，且对抗生素治疗有效。MMP通常感染德国牧羊犬，皮肤病变包括粘膜和粘膜皮肤交界处在内的皮肤持续对称性糜烂/溃疡；组织病理学镜下可见表皮下裂痕不具有CLE界面皮炎特征。

Differential diagnoses that can mimic MCLE skin lesions in dogs include mucocutaneous pyoderma (MCP) and mucous membrane pemphigoid  (MMP). MCP is a poorly characterized skin disease of dogs with greater tendency to affect the nasal planum or the perioral skin, a less erosive and more crusting phenotype, and complete response of lesions to antibiotic therapy. MMP affects German shepherd dogs commonly and the skin lesions consist of symmetric erosions/ulcers involving several mucosae and mucocutaneous junctions; histopathology reveals microscopic subepidermal clefts without interface dermatitis characteristic of CLE.

图4.犬MCLE的临床特点。（A）一只德国牧羊犬肛周糜烂并伴有外周色素沉着；（B,C）在MCLE病变中常见外阴和外阴周围多灶性红斑样糜烂，周围有色素沉着。（D）MCLE病例也可见唇周伴有结痂的红斑样糜烂。

Fig. 4. Clinical characteristics of canine MCLE. (A) Anal erosions with  peripheral hyperpigmentation in a German shepherd dog; (B, C) multifocal genital  and perigenital erythematous erosions with  peripheral hyperpigmentation are often  seen in MCLE lesions; and (D) erythematous erosions with  crusting at perilabial areas are also seen in MCLE.

实验室检测、组织病理学和免疫学评估

Laboratory,Histopathology,andImmunologicEvaluation

犬MCLE没有特异性的实验室检测方法。在最近的8只患病动物中，2只有很低的ANA滴度，未发展为SLE。目前，缺乏证据证明犬MCLE与SLE存在关系，现有针对MCLE犬的实验室检查（包括ANA血清试验）并未发现与SLE有关。

There are no specific routine laboratory findings in canine MCLE. Two of 8 patients in a recent case series exhibited very low positive ANA titers without progression to SLE. At this time, there is a lack of evidence of signs suggesting an association of canine MCLE with SLE, and the performance of extensive laboratory testing (including ANA serology) in MCLE patients to search for the latter is currently not warranted.

犬MCLE的诊断要基于病史调查和临床检查，组织病理学的特征性表现为淋巴浸润性界面性皮炎，伴有基底角质细胞损伤。界面性皮炎通常延伸至毛囊漏斗部。因为MCLE中淋巴细胞性界面性皮炎的病变会局限于小面积区域，建议在红斑和溃疡边缘多处采样进行活检。毫不奇怪的是，口腔、生殖器或面部细菌很容易在粘膜周围红斑和溃疡的MCLE病变处定殖。在一些MCLE病例的皮肤活检区域可见细菌感染，包括中性粒细胞性结痂和毛囊炎。继发的表面细菌定殖或感染会误导诊断为MCP，因而干扰病理学家的判读。所以为了避免MCLE皮肤活检中出现感染，建议外部抗菌治疗并配合或不配合全身抗生素治疗。在MCP的病例中，通过抗生素治疗所有病变都可能得到改善。几乎所有病例中，石蜡切片进行直接免疫荧染色，都能看到表皮真皮连接处有免疫球蛋白IgG的沉淀。

Diagnosis of canine MCLE is based on history and clinical presentation supported by characteristic histopathologic findings of cell-rich lymphocytic interface dermatitis with basal keratinocyte damage.7 Interface dermatitis commonly extends to the infundibula of hair follicles. Multiple biopsies at the margin of the erosions and ulcers are recommended because lymphocytic interface dermatitis in MCLE can be limited to small areas. Not surprisingly, perimucosal erosions and ulcers of MCLE lesions are easily colonized by oral, genital, or fecal bacteria; there is presence of bacterial infection, including neutrophilic crusting and folliculitis in some MCLE skin biopsy sections. These findings of secondary surface bacterial colonization or infection may complicate and bias the pathologists because they are suggestive of MCP diagnosis. Therefore, to avoid the presence of infection in MCLE skin biopsies, topical antimicrobials with or without systemic antibiotics are warranted as the first intervention. In MCP cases, complete response to antimicrobial therapy with full remission of lesions is expected to occur.Direct immunofluorescence on paraffin-embedded sections revealed immunoglobulin IgG deposition at the dermoepidermal junction in almost all cases.

治疗和结果

TREATMENTANDOUTCOME

人CLE变异型的治疗分为非药物疗法和药物疗法。非药物疗法非常重要，包括防晒（避免日照），穿防晒服并使用防晒霜。由于紫外线会诱发或加重犬水疱型CLE（VCLE）（如：夏季频繁出现突然发病），所以一旦确诊VCLE必须立刻采取防晒措施。尽管目前光照在犬CCLE发病机制中的作用仍不明确，仍建议感染犬尽可能的避免光照（犬应在早9点到晚5点间避免阳光直射）并使用防晒霜。美国皮肤病协会建议大众选择防晒系数（SPF）不小于50的防晒霜，对于患有SLE/CLE的患者，他们可以防护UV-B和UV-A。在大多数宠物店中都可以找到犬防晒霜，与人类类似，推荐SPF更高的防晒霜。

The treatment of human CLE variants is divided into nonpharmacologic and pharmacologic approaches; the nonpharmacologic approach is essential and involves photoprotective  practices  (sun avoidance) through  sunprotective  clothing  along  with proper use of sunscreen.  Because canine vesicular CLE (VCLE) skin lesions are induced and/or worsened by UV light (ie, frequent lesional flares in summer), sun avoidance is implemented immediately after a diagnosis of VCLE is made. Although the exact role of sunlight in the pathogenesis of canine CCLE variants, including GDLE and MCLE, is currently unknown, sun avoidance (keep the dogs out of direct sunlight between 9:00 AM and 5:00 PM) and the use of sunscreen, where possible, is recommended for affected dogs. The American Academy of Dermatology advises the general public to choose a sunscreen with at least sun protection factor (SPF) 50, which protects against UV-B and UV-A, in humans affected by SLE/CLE.22 Dog sunscreens are available at most pet stores and, similarly to humans, higher SPF is generally recommended.

药物治疗通过不同药物作用于CLE发病机制中的一些关键的炎性通路。2017年Cochrane系统性回顾了已发表的关于使用强效外用糖皮质激素干预人DLE疾病的文章；口服药羟基氯酮和维A酸的疗效基本相同，治愈率都为50%。研究得出结论，目前对于人CLE的研究仍处于较低水平，找到有效合适的治疗方法仍是一项挑战。接下来的挑战是对人CLE分子病理机制的更深一步的了解，以期能预测药物在机体中的作用效果。近年来在细胞学和分子水平对人CLE发病机制的研究发现，在皮肤病变中明显存在1型辅助性T细胞(TH1)淋巴浸润性炎症反应，主要表现为角质细胞的凋亡和干扰素水平上调。关于犬CLE变异型的分子学发病机制的研究很少。最近，我们报道了首次将口服免疫抑制剂霉酚酸酯用于犬表皮剥落型CLE的病变皮肤转录组，并成功治愈了皮肤病变及相关致病的细胞因子和趋化因子。患有ECLE的德国短毛指示犬的皮肤病变TH1表达强烈的淋巴浸润性炎性反应，表现为细胞凋亡和干扰素通路上调。对犬GDLE和MCLE皮肤病变分子水平发病机制的进一步理解，有利于特定生物标记物的发展，也有利于从分子水平对治疗方案进行有效性评估。

The pharmacologic therapy approach uses different medications that target some of the key inflammatory pathways involved in the pathogenesis of the CLE disease. The recent 2017 update of the Cochrane systematic review of interventions for human DLE reported evidence for the benefit of a potent topical glucocorticoid; the oral drugs hydroxychloroquine and retinoid acitretin appear to be of equal efficacy in terms of complete resolution in only 50% of patients.24 The investigators concluded overall low quality and level of reliable evidence and finding the appropriate therapy for a human CLE patient remains challenging.24 The next challenge is an in-depth understanding of the molecular pathogenesis of human CLE to be able to predict the response of medications in an individual with CLE. Recent insights into the pathogenesis of human CLE at the cellular and molecular levels revealed predominant type 1 helper T-cell (TH1) lymphocytic inflammatory response with keratinocyte apoptosis and high up regulation of interferon pathway in skin lesions.25,26  Molecular pathogenesis of canine CLE variants is poorly investigated. Recently, we  reported for the first time the lesional skin transcriptome of canine exfoliative CLE (ECLE) variant as well as successful reversal of the skin lesions and associated pathogenic cytokines/chemokines using the oral immunosuppressive medication mycophenolate. The lesional skin of a German shorthaired pointer affected with ECLE expressed strong predominant TH1 lymphocytic inflammatory response with apoptosis and up-regulation of interferon pathway.Future approaches in the understanding of the molecular pathogenesis of canine GDLE and MCLE skin lesions are warranted to enable the development of specific biomarkers and to evaluate the efficacy of therapeutic strategies at the molecular level.

口服糖皮质激素的免疫抑制剂量对犬GDLE和MCLE的皮肤病变效果良好（泼尼松/泼尼松龙1-2mg/kg），但在药物减量后大多数动物病情会复发。在最近的一篇回顾性研究中指出，GDLE皮肤病变的最佳长期治疗方案是在初始治疗时口服环孢菌素(平均剂量4.8mg/kg一天一次)，并在短期联合服用糖皮质激素。在两只GDLE患犬中，通过口服羟氯喹，同时外用0.1%他克莫司软膏的治疗方式，可缓解并控制了病变的发展。

Skin lesions of canine GDLE and MCLE seem to respond best to immunosuppressive dosages of oral glucocorticoids (1–2 mg/kg prednisone/prednisolone), but a majority of the patients experience relapses on the tapering of drug dosages.  In a recent retrospective study, the best long-term therapeutic outcome in GDLE skin lesions followed treatment with oral cyclosporine (mean 4.8 mg/kg once daily) along with a short course of glucocorticoids  at treatment onset.  The treatment modality of oral hydroxychloroquine, in conjunction with topical 0.1% tacrolimus ointment application, helped induce and maintain remission of skin lesions in 2 dogs with GDLE.

由于MCLE引起的红斑和溃疡常见于粘膜周围，并容易继发细菌定植或感染，MCLE动物一旦发现脓疱，并在皮肤细胞学检查中发现胞内菌时，应在免疫调控的同时局部使用抗生素，联合/不联合全身性抗生素治疗。在口服糖皮质激素一个月内大多数患病动物的临床症状得到完全缓解。

Because the erosions and ulcers of MCLE lesions are most commonly localized in perimucosal areas and prone to secondary bacterial colonization or infection, topical antimicrobials with or without systemic antibiotics should be applied in conjunction with immunomodulating treatments for MCLE patients where skin cytology reveals intracellular bacteria and presence of pus. In a majority of cases, oral glucocorticoids induce complete remission of clinical signs within a month of treatment induction.

由于口服糖皮质激素剂量的减少常会导致MCLE皮肤病变复发，联合使用四环素类抗生素，或配合烟碱酰胺在长期治疗中得到了相当好的疗效。局部使用他克莫司或增加全身性免疫抑制药物（硫唑嘌呤、环孢菌素、霉酚酸酯等），长期控制MCLE发展的治疗方案还需要进一步的评估。

Because the tapering of  oral glucocorticoids  commonly  leads to  the relapse of MCLE skin lesions, a long-term beneficial response can be achieved using a combination of a tetracycline antibiotic, with or without niacinamide, in some dogs.7,9  The usefulness of adding topical tacrolimus or additional systemic immunosuppressive drugs (azathioprine, cyclosporine,  mycophenolate  mofetil, and so forth) for longterm control of MCLE disease should be evaluated further.

总结

SUMMARY

由于在近20年中，犬CLE变异型的种类已经明显增加，兽医应更熟悉CLE变异型的典型临床特征，以获得早期诊断并给予合适的治疗。尽管GDLE和MCLE的临床表现不同，但其确诊应根据感染部位的皮肤活检结果，表现为富含细胞的界面性皮炎。多种治疗方法对犬GDLE和MCLE的皮肤病变都有效果，但有些病例在药物剂量减少后病情复发。同时也推荐防晒。

Because the spectrum of canine CLE variants has expanded markedly in the recent 2 decades, veterinarians are encouraged to become familiar with the characteristic clinical features of CLE variants to permit early diagnosis and appropriate treatment. Although the presentations of GDLE and MCLE are clinically distinct, a definitive diagnosis relies on the demonstration of a cell-rich interface dermatitis in skin biopsies taken from affected areas. Skin lesions of canine GDLE and MCLE seem to respond to a wide range of treatments, but half of the cases experienced relapse on the tapering of drug dosages. Sun avoidance is also recommended.

陈逗逗啊

廊坊永鑫罗玄

王帆

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