犬皮肤红斑狼疮：一项综合性评估（5）-黏膜皮肤红斑狼疮

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


Mucocutaneous lupus erythematosus
黏膜皮肤红斑狼疮
Historical perspective In the mid 1990’s, two German shepherd dogs (one in France and one in Québec,Canada) were described as having a genital-predominant DLE.In 1998, we proposed the disease name of MCLE for dogs with perimucosal ulcerative lesions and microscopic characteristics of CLE (Olivry T: British Veterinary Dermatology Study Group, York, 1998).Additional cases with identical phenotypes were later published with the diagnoses of MCLE , DLE ,or, more recently, perianal/perivulvar LE . Finally, we reported a large series of 21 additional dogs with MCLE was reported in 2015 and a single case report from Chile was later published in 2017.
历史背景 在20世纪90年代中期，两只德国牧羊犬（一只在法国，另一只在加拿大魁北克省）被认为是患有主要为生殖器病变的盘状红斑狼疮。在1998年，我们提出了关于犬的MCLE（黏膜皮肤红斑狼疮）的疾病名称，显示了黏膜周溃疡病变和皮肤红斑狼疮的显微镜特征（Olivry T：1998年，来自约克大学，英国兽医皮肤病学研究小组）。另外有相同表型的病例相继发表，诊断为黏膜皮肤红斑狼疮、盘状红斑狼疮或最近提出的肛周/外阴周红斑狼疮。最后，我们在2015年报道了包含另外21只患有黏膜皮肤红斑狼疮犬的一个大型病例报告，在2017年发表了来自智利的单一病例。

Incidence and prevalence There are no available data to estimate the incidence of prevalence of MCLE in dogs.
发病率和流行率 没有可靠数据来评估犬黏膜皮肤红斑狼疮的发病率和流行率。

Signalment Collating the signalment of all published cases of canine MCLE yielded pertinent information. Of the 36 dogs , there were 17 German shepherd dogs and their crosses (47%); adding the two Belgian shepherds leads to about half of the dogs with MCLE belonging to breeds related to German shepherds. Altogether, females appear nearly twice over-represented with a female-to-male ratio of 1.8; there was an equal representation of intact and neutered individuals. Interestingly, this female-to-male ratio increases to 3.8 if we only collate data from German/Belgian shepherds and their crosses. In all, the age of onset of skin lesions of MCLE varied between 3 to 13 years (median and means: 6 years). Most dogs for which this information was available (17/28; 61%) began exhibiting noticeable mucocutaneous lesions in mid-adulthood (i.e. between 4 and 8 years of age).
特征 整理了所有已发表的犬黏膜皮肤红斑狼疮病例的特征，得出了相关的信息。在36只犬中，有17只德国牧羊犬及其杂交犬（47%）；加上两只比利时牧羊犬，导致了约一半的患有黏膜皮肤红斑狼疮的犬有德国牧羊犬的血统。总的来说，雌性的比例几乎超过了两倍，雌雄比例是1.8；绝育与未绝育的比例相当。有趣的是，我们仅整理德国/比利时牧羊犬及其杂交犬数据时，雌雄比例可增至3.8。总之，黏膜皮肤红斑狼疮的皮肤病变的发病年龄在3至13岁之间（中位和平均年龄是6岁）。据可靠信息显示大多数犬开始表现明显的黏膜病变在成年中期（即4至8岁间）。

Odds ratios for breed, sex or age predispositions for the development of MCLE cannot be estimated, as dogs come from multiple continents (North and South America, Japan, Europe), and a reference population therefore is not available.
由于犬来自多个大陆（北美和南美、日本、欧洲），无法估计黏膜皮肤红斑狼疮的品种、性别或年龄倾向的优势比，因此无法获得可参考的总体数量。

Clinical signs The owners of dogs with MCLE often report perimucosal ulcerative skin lesions with vocalization suggesting pain why defecating or urinating.
临床症状 患有黏膜皮肤红斑狼疮犬的主人通常报告说有黏膜周皮肤病变时会通过大小便时发出声音来暗示疼痛。
  
At the time of presentation to the veterinarian, lesions have been reported to occur most commonly on or around the anus (24/36; 67%) (Fig. 7a) or on the genitalia or region (17/36, 47%) (Fig. 7b,c).Similar lesions can also be seen, but less commonly, abutting the lips, but they usually do not cross into the mucosa itself (10 dogs; 28%) (Fig. 7e,f). More rarely, lesions have been noted around the eyes (6 dogs; 17%) (Fig. 7d) and nasal planum (4 dogs; 11%);oral lesion are rarest (3 dogs; 9%) . In the largest case series, most dogs had two or more areas affected, and the lesions were usually symmetrically distributed .
在向兽医描述时最常见的病变出现在肛周（24/36；67%）（图7a）或生殖器或生殖器周围区域（17/36；47%）（图7b、c）。相似的病变也可以看到，但不太常见的是唇部附近，通常不侵入黏膜（10只犬；28%）（图7e、f）。更罕见的病变是在眼周（6只犬；17%）（图7d）和鼻平面（4只犬；11%）；口腔病变最罕见（3只犬；9%）。在最大病例系列中，大多数犬有两个或两个以上区域受到影响，且病变通常对称分布。
  
The characteristic lesions of MCLE are erosions and ulcers(Fig. 7a-f), but the latter do not tend to heal with scarring , an important difference with the lesions of facial and generalized DLE. Crusts are present when lesions extend into haired skin. Hyperpigmentation can be seen often around ulcerative lesions or at the site of previous ones, thus leaving a figurate or reticulated pattern. Pruritus is normally absent or mild, but pain is described when defecating and urinating or when touching the lesions; systemic signs have not been reported.
黏膜皮肤红斑狼疮的病变特征是糜烂和溃疡（图7a-f），但溃疡通常不会瘢痕愈合，这是与面部和全身型盘状红斑狼疮病变重要的不同之处。当病变延伸到有被毛的皮肤区域时，就会出现结痂。色素沉着通常可以在溃疡病变周围或陈旧的病变区域，形成花纹状或网状图案。通常不瘙痒或轻度瘙痒，但当大小便或触碰病变时是疼痛的；全身性特征尚未报道。
  
The most relevant clinical differential diagnoses of MCLE are mucocutaneous pyoderma (MCP), MMP and EM variants.
最近黏膜皮肤红斑狼疮临床鉴别诊断是黏膜皮肤脓皮病（MCP）、黏膜类天疱疮和多形红斑的变异型。

Histopathology In the largest case series, and per inclusion criteria, skin biopsies contained a cell-rich lymphocytic interface dermatitis with basal keratinocyte damage (i.e. basal cell apoptosis, loss and/or hydropic degeneration)(Fig. 8a-c).This pattern was often patchy, or in limited areas, sometimes only being observed at close proximity to an ulcer margin.Interface dermatitis commonly extended to the infundibula of hair follicles (Fig. 8d), while inferior segments of hair follicles are sometimes also involved (Fig. 8e). Basement membrane thickening was found to be multifocal, patchy to diffuse (Fig. 8c). Pigmentary incontinence varied from mild to marked. Plasma cells were present in all cases (Fig. 8b,c),mixed with lymphocytes and were often numerous in subepidermal, perivascular, periadnexal and in dermal areas below erosions and ulcers. Erosions and ulcers were common but granulation tissue was limited and fibrosis (scarring) was not seen. Occasional suprabasal keratinocyte apoptosis was noted in half of the cases, but suprabasal lymphocytic satellitosis, when present, was always mild.Nonetheless, superficial keratinocyte cell death can lead to confusion with EM and morphologically related conditions.Not surprisingly, for a perimucosal ulcerative disease, lesions of concurrent bacterial infection were common, including neutrophilic crusting, pustules, perifolliculitis and folliculitis, as well as presence of bacteria in surface exudates. Such infection will complicate the histological diagnosis and the successful treatment of pyoderma is warranted prior to biopsy.
组织病理学 在最大的病例报告里，每个入选病例标准包括，皮肤活检包含了富含细胞的淋巴细胞界面性皮炎，伴随着基底角质细胞损伤（即基底细胞凋亡、丢失和/或水样变性）（图8a-c）。这种模式通常是片状的，或在有限的区域，有时只在靠近溃疡边缘的地方观察到。界面性皮炎通常会延伸到毛囊漏斗部（图8d），有时也会延伸至毛囊下部（图8e）。基底膜增厚呈多灶性、片状扩散（图8c）。色素失禁中度到重度不等。所有病例中都存在浆细胞（图8b、c），混合着淋巴细胞，常见于表皮下、血管周围、附件周围和真皮下的糜烂和溃疡。糜烂和溃疡常见，但肉芽组织见少量，未见纤维化（瘢痕）。在一半的病例中，偶尔出现基底上层角质细胞凋亡，但可能存在轻微的基底上层淋巴细胞卫星现象。但是浅表性角质细胞死亡可能导致与多形红斑和形态相关的情况混淆。对于黏膜周溃疡，病变同时出现细菌感染是很常见的，包括中性粒细胞结痂、脓疱、毛囊周炎和毛囊炎，以及表面渗出物出现细菌。这种感染使组织学诊断变复杂了，在活检前有必要治疗脓皮病。

Immunopathology In dogs in whom this information was reported, direct IF almost always revealed a positive IgG lupus band test (LBT) . Positive LBTs were sometimes also uncovered for IgA, IgM and C3. Positive ANA titers were rarely found, however.
免疫病理学 在报道这一信息的犬中，直接免疫荧光法几乎总是显示lgG狼疮带试验（LBT）阳性。LBTs阳性结果也发现于lgA、lgM和C3中。然而，抗核抗体滴度阳性很罕见。


Treatment and outcome The skin lesions of canine MCLE appear to respond best to immunosuppressive dosages of oral glucocorticoids.The complete remission of signs is generally obtained within one month of treatment induction. A combination of a tetracycline antibiotic, with or without niacinamide, appears beneficial either alone or as adjunctive combination in some dogs. In most patients, the tapering of oral glucocorticoids leads to the prompt relapse of skin lesions, which will undergo remission once the dosage is re-escalated again. The usefulness of adding additional immunosuppressive drugs (e.g. azathioprine, ciclosporin, mycophenolate mofetil etc.) to permit the reduction of oral glucocorticoid doses needs further investigations.
治疗和预后 犬黏膜皮肤红斑狼疮的皮肤病变似乎对使用免疫抑制剂量口服糖皮质激素反应最好。一般在治疗一个月后症状完全缓解。在一些犬中四环素类抗生素和烟酰胺的单独或联合使用似乎有效。在大多数病患中，减少口服糖皮质激素的剂量会导致皮肤病变快速复发，一旦剂量再次提高，病情又会缓解。为了减少口服糖皮质激素的剂量而添加其他的免疫抑制剂（如：硫唑嘌呤、环孢菌素、吗替麦考酚酯等），这需要进一步研究。



Fig. 7 Clinical characteristics of canine mucocutaneous lupus erythematosus.
a: anal erosions with peripheral hyperpigmentation in a German shepherd dog;
(b): multifocal perigenital erosions with peripheral hyperpigmentation are often seen in female German shepherd bitches;
(c):erosions on the lateral sides of the vulva in a German shepherd bitch (courtesy of Pablo Del Mestre, Mar Del Plata Argentina);
(d): periocular erosions in a German shepherd–these lesions were bilateral (courtesy of Petra Bizikova, NC State University, Raleigh;
(e): erosion abutting the lip in the same German shepherd dog as in (a);
(f): same dog as in (b) – large perilabial erosion; this lesion was also symmetric

图7黏膜皮肤红斑狼疮的临床特征
a：一只德国牧羊犬肛门糜烂，伴随肛周色素沉着过度；
(b)：在雌性德国牧羊犬上常见多灶性生殖器周围糜烂，伴随着外周色素沉着过度；
(c)：一只雌性德国牧羊犬外阴外侧糜烂（由阿根廷马德普拉塔Pablo Del Mestre提供）；
(d)：一只德国牧羊犬眼周糜烂-这些病变两侧眼周都有（由北卡罗莱纳州立大学罗利市Petra Bizikova提供）；
(e)：(a)中的德国牧羊犬，唇周糜烂；
(f)：(b)中的德国牧羊犬，唇周大面积糜烂；这些病变也是对称的

Fig. 8 Histopathology of canine mucocutaneous lupus erythematosus.

a: cell-rich, lymphocytic interface dermatitis is present with numerous plasma cells, including Mott cells, which is common with inflammation in perimucosal skin and is exacerbated by secondary bacterial infection.100X

(b): inset box from image “a”, lymphocytes infiltrate the basal and suprabasal layers of the epidermis in association with multifocal basal cell apoptosis. 400X

(c): basement membrane thickening (arrows) is present and is usually patchy and multifocal. 400X (d): lymphocytic interface folliculitis and mural folliculitis involve the infundibulum and extend to the isthmus (not shown) of a hair follicle. 400X

(e): lymphocytic mural folliculitis of the inferior hair follicle (external root sheath), with apoptosis and follicular atrophy. 200X

图8犬黏膜皮肤红斑狼疮的组织病理学

a：存在富含细胞、淋巴细胞界面性皮炎，伴随着许多浆细胞，包括莫托细胞，这是常见的黏膜周皮肤炎症，并加剧继发的细菌感染。100X

(b)：“a”中方框部分，淋巴细胞浸润表皮基底层和基底上层，与多灶性基底细胞凋亡有关。400X

(c)：基底膜增厚（箭头处），通常呈片状和多灶性。400X

(d)：淋巴细胞界面性毛囊炎和毛囊壁炎，涉及到毛囊漏斗部，并延伸到毛囊的峡部（未显示）。400X

(e)：淋巴细胞毛囊壁炎毛囊下部（外根鞘），伴随着细胞凋亡和毛囊萎缩。200X

王帆

感谢辛蕾同学的精彩翻译~