犬皮肤红斑狼疮：一项综合性评估（3）-亚急性皮肤红斑狼疮

王帆

Cutaneous lupus erythematosus in dogs: a comprehensive review

犬皮肤红斑狼疮：一项综合性评估
作者：Thierry Olivry , Keith E. Linder and Frane Banovic


翻译：辛蕾  校对：王帆

Lupus-specific skin diseases
特异性狼疮皮肤病
The salient features of lupus-systemic skin diseases in dogs are summarized in Table 1.
表1总结了系统性狼疮皮肤病的显著特征。

Subacute cutaneous lupus erythematosus
亚急性皮肤红斑狼疮
Vesicular cutaneous lupus erythematosus
水疱型皮肤红斑狼疮
Historical perspective
历史背景
First recognized in the late 1960’s, “hidradenitis suppurativa”was a unique skin disease described in Collies, Shetland sheepdogs and their crosses. Since the early 1980’s, the disease mentioned above was suspected to represent, in fact, bullous pemphigoid or erythema multiforme in these breeds. In 1995, an "idiopathic ulcerative dermatosis of Collies and Shetland sheepdogs" was individualized as a separate entity that was initially linked to juvenile dermatomyositis, also seen in these breeds. In 2001, Jackson and Olivry separated this ulcerative dermatosis from dermatomyositis based on clinical and histological grounds, and the denomination of VCLE was then coined.In 2004, the same authors reported the detection of circulating anti-Ro autoantibodies in dogs with VCLE,and they highlighted the similarity of this canine disease with human SCLE.
20世纪60年代末首次承认在柯利牧羊犬、喜乐蒂牧羊犬及他们的杂交品种上“化脓性汗腺炎”是一种独特的皮肤病。自20世纪80年代初以来，怀疑上述提及的疾病，事实上是这些品种中的大疱型类天疱疮或多形红斑。在1995年，一种“柯利牧羊犬和喜乐蒂牧羊犬的特发性溃疡性皮肤病”被单独列出，最初跟幼年型皮肌炎有关，也会出现在这些品种中。在2001年，Jackson和Olivry根据临床和组织学将这种溃疡性皮肤病与皮肌炎区分开来，然后命名为水疱型皮肤红斑狼疮VCLE。在2004年，同样的作者报告了在犬水疱型皮肤红斑狼疮中检测到了循环中的抗Ro自身抗体，并且他们强调了这种犬的疾病与人亚急性皮肤红斑狼疮的相似性。

Incidence and prevalence
发病率和流行率
At this time, there is insufficient information on canine VCLE to appropriately assess the incidence and prevalence of this disease in dogs. However, this entity has been diagnosed in several countries and continents over the last five decades.
目前，关于犬水疱型红斑狼疮的信息不足，无法适当评估这种疾病在犬中的发病率和流行率。然而，在过去的五十年中，这一疾病已在若干国家和城市得到确诊。

Signalment
特征
The clinical characteristics of canine VCLE can be inferred from six reports including 25 dogs. Among these cases, there were 11 Shetland sheepdogs and their crosses(44%), seven (rough) collies (28%) and seven pure- or cross-bred border collies (28%). The female-to-male ratio was 0.9 and the age of onset varied between 2.0 and 11.0 years of age (median 5.5 years). That VCLE has been recognized almost entirely in collie-related breeds suggests the existence of a strong genetic predisposition, but the genetics of this disease have not yet been elucidated.
犬水疱型皮肤红斑狼疮的临床特征可以从包括25只犬在内的六份报告中推断出来。在这些病例中，有11只喜乐蒂牧羊犬及其杂交犬（44%）、7只（粗毛）柯利犬（28%）和7只纯种或杂交的边境牧羊犬（28%）。雌雄比例是0.9，并且首次发病年龄在2-10岁间（中位年龄5.5岁）。水疱型皮肤红斑狼疮几乎完全是柯利牧羊犬的专属，这表明存在一种强烈的遗传倾向，但这种疾病的遗传学并没有阐明。

Clinical signs
临床症状
Dogs with VCLE present with erythema and flaccid vesicles that slough to leave erosions and ulcers; these predominate on glabrous skin of the abdomen, axillae, groin and medial thighs. Skin lesions exhibit a unique sharp-edged annular, polycyclic or serpiginous pattern (Fig. 2a-d). There is accompanying ulceration of mucocutaneous junctions (Fig. 2e,f), concave pinnae and oral cavity in some patients, but these nonventral lesions are usually minor in extent and severity . The secondary bacterial colonization of erosive/ulcerative lesions is common. Altogether, these lesions resemble those of the vesicular variant of human SCLE. Pruritus manifestations are usually absent, except, perhaps, for a licking of eroded lesions .
患有水疱型皮肤红斑狼疮的犬会出现红斑和松弛性水疱，脱落后形成糜烂和溃疡；主要存在于腹部、腋下、腹股沟、大腿内侧这些无毛皮肤区域。皮肤病变呈现出一种独特的边界清晰的环形、多环形或波形（图2a-d）。伴随着黏膜皮肤交界处的溃疡灶，有些病患在耳廓凹面和口腔也有（图2e、f），但这些非腹侧病变通常范围小且严重程度较轻。糜烂/溃疡病变常出现继发性细菌增殖。总之，这些病变类似于人亚急性皮肤红斑狼疮的水疱型变异型。通常不存在瘙痒表现，除了可能是舔舐的病变。
  
In eight of 11 (73%) dogs with VCLE, clinical signs were reported to first arise in the summer. In three cases where this information was available, lesions recurred during summer months. Systemic signs are typically not seen in dogs with VCLE, though one dog was reported with weakness and lethargy with associated electromyographic changes interpreted as myositis. There are normally no relevant hematology and clinical biochemistry changes.
在11只患有水疱型皮肤红斑狼疮的犬中，有8只（73%）报道在夏季首次出现临床症状。在三例信息可靠的病例中，病变在夏季复发。全身性症状通常不会在患有水疱型皮肤红斑狼疮的犬身上出现，尽管有一只犬被报道有虚弱和嗜睡，相关的肌电图变化说明是肌炎。通常没有血液学和临床生化方面的变化。

The main dermatosis with clinical signs VCLE is erythema multiforme and its variants.
临床症状与水疱型皮肤红斑狼疮相似的主要皮肤病是多形红斑及其变异型。





Histopathology
组织病理学
In canine VCLE, a lymphocyte cell-rich interface dermatitis is associated with prominent basal keratinocyte vacuolation,apoptosis and loss, which is often sufficient to cause intrabasal clefts and epidermal vesiculation, typical of the disease(Fig. 3a-c). Basal cell apoptosis is reported to be as high as 16 apoptotic basal cells per 1 mm of epidermis utilizing immunohistochemical detection methods. Hair follicle infundibula have a similar lymphocytic interface and mural folliculitis. Pigment dispersal to dermal macrophages(pigmentary incontinence) is often not a feature or is very mild, likely due to breed coat coloration and the tendency for lesions to occur in poorly- or non-pigmented skin. The thickening of the basement membrane zone and superficial dermal fibrosis are uncommon, which is attributable to the subacute nature of the disease, but they can occur in persistent lesions (Fig. 3d). Cell-rich lesions dominate biopsies but very mild lymphocytic dermal infiltrates or even cell-poor areas of lesions can occur that lack a subepidermal, band-like (lichenoid), dermal infiltrate of lymphocytes(Fig. 3c).Cell-poor areas of lesions can lead to confusion with juvenile dermatomyositis, which is seen often in the same breeds. Dermatomyositis presents with lesions of ischemic dermatopathy (i.e. cell-poor interface dermatitis and ischemic follicular atrophy), but cell-poor VCLE lesions have more lymphocyte exocytosis into the basal epidermal layer, with lymphocytic satellitosis of apoptotic basal keratinocytes. If the intrabasal level of epidermal clefts is not recognized (Fig. 3b), then vesiculation can be confused with subepidermal autoimmune blistering skin diseases such as mucous membrane pemphigoid (MMP), bullous pemphigoid (BP) and epidermolysis bullosa acquisita(EBA). The prominence of basal apoptosis and intrabasal epidermal vesiculation, when present, supports the histological diagnosis of VCLE over that of other variants of CCLE, but this distinction is difficult for more chronic lesions and is best done clinically, as for all forms of canine CLE. Occasionally superficial epidermal apoptosis with lymphocytic satellitosis might erroneously suggest the diagnosis of erythema multiforme and its morphologically related conditions. Neutrophilic inflammation is common in lesions that progress to ulcers and support the development of secondary bacterial infection.
在犬水疱型皮肤红斑狼疮中，富含淋巴细胞的界面性皮炎与显著的基底层角质细胞空泡化、细胞凋亡和丢失有关，往往引起基底内开裂和表皮水疱形成，这是该疾病的典型反应（图3a-c）。据报道，利用免疫组化检测方法，每1mm表皮中基底细胞凋亡高达16个。毛囊漏斗部有相似的淋巴细胞界面性皮炎和毛囊壁炎。色素扩散到真皮巨噬细胞（色素失禁）往往不是一个特征或是反应比较轻微，可能是由于品种被毛着色和病变倾向于发生在色素较少或无色素的皮肤部位上。基底膜区增厚和真皮浅表纤维化是罕见的，这可归因于疾病的亚急性性质，但它们可能会发生持续性的病变（图3d）。活检主要以细胞丰富的病变部位为主，但也会出现非常轻微的淋巴细胞性真皮浸润，甚至是在表皮缺失区域出现乏细胞性病变区域，以及带状（苔藓样变）、真皮淋巴细胞浸润（图3c）。乏细胞病变区域可能会与幼年型皮肌炎混淆，这通常见于同一个品种。皮肌炎表现为缺血性皮肤病病变（如：乏细胞界面性皮炎和缺血性毛囊萎缩），但乏细胞水疱型皮肤红斑狼疮的病变有更多的淋巴细胞通过细胞外排作用进入表皮基底层，伴随着基底角质细胞凋亡的淋巴细胞性卫星现象。如果不能识别基底内表皮开裂水平，那么水疱形成可能会与表皮下自体免疫性水疱型皮肤病如黏膜类天疱疮（MMP）、大疱性类天疱疮（BP）和获得性大疱性表皮松懈症（EBA）混淆。当出现明显的基底细胞凋亡和表皮基底层内水疱形成时，支持水疱型皮肤红斑狼疮的组织学诊断，而不是慢性皮肤红斑狼疮的其他变异型，但这点对于鉴别更多慢性病变是比较困难，最好在临床上进行，就像所有种类的犬皮肤红斑狼疮一样。偶有浅表表皮细胞凋亡伴有淋巴细胞卫星现象，可能错误地认为是多形红斑的诊断及其形态学的相关情况。中性粒细胞炎症是常见的病变，随后发展为溃疡并促进了继发的细菌感染。


Immunohistochemistry
免疫组化
In one of the two largest case series, detailed information on mononuclear cell immunophenotyping was reported. T-lymphocytes expressing CD3 were found in epidermal sections of all 11 dogs examined. In two of these dogs with VCLE, the phenotype of skin-infiltrating leukocytes was similar: approximately 25 to 50% of epidermal leukocytes were T-lymphocytes expressing the alpha-beta T-cell receptor, CD3 and CD8; less commonly, epitheliotropic lymphocytes expressed CD4. The other epithelial leukocytes were identified as CD1-positive Langerhans cells. In the superficial dermis, infiltrating cells consisted of an approximately equal population of alpha-beta T-lymphocytes expressing CD4 or CD8-alpha and CD1-positive dermal dendritic cells. Rare CD21-positive B-lymphocytes were detected in the superficial dermis. In contrast, gamma-delta T-cells were not identified in either the epidermis or dermis. Basal keratinocytes expressed high levels of ICAM-1 and low levels of class II major histocompatibility complex molecules signifying their activated state. In this study,apoptotic keratinocytes were observed in the basal epidermis of seven of the 12 dogs evaluated (58%).
两份大型病例报告其中之一，报道了关于单核细胞免疫分型的详细信息。在11只犬的表皮切片中发现表达CD3的T淋巴细胞。在其中两只患有水疱型皮肤红斑狼疮的犬中，皮肤浸润白细胞的类型相似：约25%至50%的表皮白细胞是表达α-β的T细胞受体、CD3和CD8的T淋巴细胞；不太常见的是上皮细胞表达的CD4。其他上皮白细胞被确认为CD1阳性的朗格罕细胞。在浅表真皮中，浸润细胞由大概同等数量的表达CD4或CD8-α的α-βT淋巴细胞和CD1阳性的真皮树突状细胞组成。罕见的CD21阳性的B淋巴细胞在浅表真皮被发现。相反，γ-δT细胞在表皮或真皮中没有被发现。基底角质细胞表达高水平的ICAM-1和低水平的II类主要组织相容性复合体分子，表明其活化状态。在本研究中，在12只被评估的犬中，7只（58%）在基底表皮中观察到凋亡的角质细胞。

Immunopathology
免疫病理学
Direct immunofluorescence Direct immunofluorescence revealed the presence of IgG at the basement membrane zone in 7/14 (50%) dogs with VCLE. The deposition of IgG around blood vessels was observed in 13/14 dogs (93%). Finally, cytoplasmic basal keratinocyte IgG was detected in 6/14 subjects (43%); the deposition of activated complement was not seen .
直接免疫荧光法 直接免疫荧光显示在14只患有水疱型皮肤红斑狼疮的犬中有7只（50%）在基底膜区域存在lgG，有13只（93%）观察到lgG在血管周沉积，最后有6只（43%）检测到细胞质基底角质细胞lgG；未见活化的补体沉积。
                                                                                                                                      Indirect immunofluorescence Indirect immunofluorescence did not reveal anti-basement membrane circulating IgG autoantibodies in the serum of five dogs with VCLE. Similarly circulating antinuclear IgG autoantibodies were not detected in the serum of any of 11 dogs with VCLE using human Hep2 cells as a substrate .
间接免疫荧光法 间接免疫荧光在五只患有水疱型皮肤红斑狼疮的犬血清中不显示抗基底膜循环lgG自身抗体。以人Hep2细胞为底物，在11只患有水疱型皮肤红斑狼疮的犬血清中未发现类似的循环抗核lgG自身抗体。

Immunoblotting and ELISA Using Hep2 cell extracts,immunoblotting permitted the detection of autoantibodies against soluble nuclear antigens in 9/11 tested sera (82%). When an ELISA was performed with purified human soluble nuclear antigens, the serum from 8/11 dogs with VCLE (73%) was found to have IgG autoantibodies that bound to these antigens. Antibodies were found to target Ro/SSA (45% of dogs), La/SSB (45%), Sm/RNP (45%), Scl70(36%), Jo-1 (36%) and Sm-SnRNP (18%) . Overall, and as seen in humans with SCLE, most dogs with VCLE (6/11;55%) were found to have IgG antibodies that targeted Ro/SSA and/or La/SSB antigens .
免疫印迹法和酶联免疫吸附测定 使用Hep2细胞提取物，免疫印迹法可以在9/11（82%）的检测血清中发现抗可溶性核抗原的自身抗体。当用纯化人的可溶性核抗原进行ELISA时，8/11（73%）的患有水疱型皮肤红斑狼疮犬的血清中被发现具有与这些抗原结合的lgG自身抗体。发现抗体靶向Ro/SSA (45%的犬)、 La/SSB (45%),、Sm/RNP (45%)、Scl70(36%)、Jo-1 (36%)和Sm-SnRNP (18%)。总体来说，正如在患有亚急性皮肤红斑狼疮的人类中所看到的，大多数患有水疱型皮肤红斑狼疮的犬（6/11，55%）发现具有针对Ro/SSA和/或La/SSB抗原的lgG抗体。

Treatment and outcome
治疗和预后
As VCLE is induced and/or worsened by UV light, sun avoidance should be implemented immediately after a diagnosis is made. The first case series provided detailed information on the post-treatment outcome in 11 dogs with VCLE . In six of these dogs (55%), clinical signs resolved with the oral administration of prednisone at low immunosuppressive dosages (2 mg/kg/day), which were tapered according to treatment response. In three dogs(27%), azathioprine (at about 2 mg/kg/day) was added to the treatment regimen due to the insufficient reduction of lesions with glucocorticoids. Finally, the response to pentoxifylline (initially prescribed due to the then erroneous inclusion of VCLE in the dermatomyositis spectrum) was reported as poor in four dogs (36%). In this case study of 11 dogs, one (9%) died of unknown cause, and three (27%) were euthanized at the owner’s request due to poor response to treatment. In the remaining seven dogs (64%), a complete or sub-complete remission of signs was achieved with glucocorticoids alone or in combination with azathioprine . Lesions have also been shown to respond to the immunosuppressant mycophenolate mofetil in one rough collie with VCLE, as the introduction of this drug led to the complete remission of skin lesions after the discontinuation of oral glucocorticoids.
由于水疱型皮肤红斑狼疮是因紫外线光引起和/或恶化的，应在作出诊断后立刻进行防晒。第一个病例报道提供了关于11只患有水疱型皮肤红斑狼疮的犬治疗后预后的详细信息。在其中六只犬（55%）中，临床治疗方式是以低免疫抑制剂量（2mg/kg/d）口服泼尼松，根据临床反应逐步减量。在三只犬（27%）中，由于糖皮质激素对于缓解病情的不足，同时使用了硫唑嘌呤（约2mg/kg/d）。最后，己酮可可碱的疗效（最初是由于当时错误地将水疱型皮肤红斑狼疮归入了皮肌炎）在四只犬（36%）中很差。在本病例研究中，11只犬中有一只（9%）死于不明原因，有三只（27%）因疗效不佳而在主人要求下安乐。在其余七只犬（64%）中，糖皮质激素单独使用或与硫唑嘌呤联合使用可以使病情部分或完全缓解。在一只患有水疱型皮肤红斑狼疮的粗毛柯利牧羊犬中对免疫抑制剂吗替麦考酚酯也有反应，因为在停止口服糖皮质激素后使用该药物使病情完全缓解。
  
More recently, the benefit of calcineurin inhibitors, which had been previously reported in two dogs with VCLE, was confirmed in 11 additional patients . In all dogs, treatment was initiated with sun avoidance, oral glucocorticoids and oral ciclosporin at a median dosage of 5.5 mg/kg/day. A complete remission of skin lesions occurred in 8/11 dogs (73%) within one to two months of starting treatment. In two dogs (18%), lesion remission was achieved by increasing the dose of ciclosporin and adding topical 0.1% tacrolimus ointment. While relapses of clinical signs were common when the dosage of ciclosporin was lowered, the long-term remission of signs was possible with calcineurin inhibitors, either alone or in combination. These observations suggest that calcineurin inhibitors might be the drug category of choice to treat canine VCLE.
钙调磷酸酶抑制剂以前曾在两只患有水疱型皮肤红斑狼疮的犬中报道过，最近在另外的11个病患中被证实有效。在所有犬中，治疗开始就进行防晒处理，以中位剂量5.5mg/kg/d口服糖皮质激素和环孢菌素。在一到两个月的治疗后，11只犬中有8只（73%）病情完全缓解。2只犬（18%）通过增加环孢菌素剂量和使用0.1%他克莫司软膏使病情缓解。当环孢菌素剂量降低时，病情常会复发，但钙调磷酸酶抑制剂可以单独或联合使用来长期缓解病情。这些表明了钙调磷酸酶抑制剂可能会成为治疗犬水疱型皮肤红斑狼疮的首选药物。







Fig. 2 Clinical characteristics of canine vesicular cutaneous lupus erythematosus.
a, b, c: erythematous macules progress to annular-to-polycyclic lesions with central flaccid vesiculation and peripheral erythema; skin lesions predominate on the ventral abdomen, medial thighs and axillae.
d: with chronicity, ulceration can become more prominent.
e, f: erosions at mucocutaneous junctions can be seen in some dogs
图2犬水疱型皮肤红斑狼疮的临床特点
a、b、c：红斑发展为环形至多环形病变，伴随着中央松弛性水疱和外周红斑；皮肤病变主要分布在腹侧部、大腿内侧和腋下。
d：伴随着慢性病程，溃疡会更加明显。
e、f：在一些犬身上可见皮肤黏膜交界处的糜烂





Fig. 3 Histopathology of canine vesicular cutaneous lupus erythematosus.
a: cell-rich, lymphocytic interface dermatitis is present. Marked basal keratinocyte apoptosis has caused a secondary cleft (vesiculation) through the epidermal basal cell layer, which is typical of the disease. 100X
(b):inset box from image “a”, lymphocytes infiltrate the basal layer and are associated with basal cell vacuolation, apoptosis, loss and disorganization at the cleft margin. 200X
(c): dermal lymphocytic inflammation can be mild, lacking a clear subepidermal band-like (lichenoid) pattern, but lymphocytes are still observed in the basal epidermal layer in association with basal cell loss. 200X
(d): chronic lesions can develop epidermal hyperplasia, a prominent dermal infiltrate of lymphocytes and plasma cells and thickening of the basement membrane zone. 200X
图3犬水疱型皮肤红斑狼疮的组织病理学
a：细胞丰富的淋巴细胞交界性皮炎。标记的基底角质细胞凋亡通过表皮基底细胞层引起继发性开裂（水疱形成），这是疾病的典型反应。100X
(b)：“a”中方框部分，淋巴细胞浸润基底层并与基底细胞空泡化、凋亡、丢失和开裂边缘结构紊乱相关。200X
(c)：轻微的真皮淋巴细胞炎症，缺乏一个清晰的表皮下带状（苔藓样变）模式，但与基底细胞丢失有关的表皮基底层仍可观察到淋巴细胞。200X
(d)：慢性的病变可发生表皮增生，明显的淋巴细胞和浆细胞真皮浸润和基底膜区域增厚。200X

王帆

感谢辛蕾同学的精彩翻译~

李慧晓

精彩，需要反复看几遍加深印象！！！