标题: 犬皮肤红斑狼疮：一项综合性评估（4）-慢性皮肤红斑狼疮 [打印本页] 作者: 王帆 时间: 2020-5-27 10:16 标题: 犬皮肤红斑狼疮：一项综合性评估（4）-慢性皮肤红斑狼疮 [attach]58266[/attach] 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
Chronic cutaneous lupus erythematosus 慢性皮肤红斑狼疮 Exfoliative cutaneous lupus erythematosus 表皮剥脱型皮肤红斑狼疮 Historical perspective 历史背景
In 1992, Ihrke, Gross and Walder described a scaly dermatosis in young German shorthaired pointers (GSHP).Because microscopic lesions resembled those seen in subjects with lupus, the disease was named “hereditary lupoid dermatosis”.One brief case report , one series of five cases and a book chapter constituted the early descriptions of this rare disease.
在1992年，Ihrke、Gross和Walder描述了在青年德国短毛指示犬（GSHP）上的一种皮屑性皮肤病。由于显微镜下的病变与狼疮类似，这种疾病被命名为“遗传性类狼疮皮肤病”。一份简短的病例报告、一份报告的五个病例和一个书章构成了对此种罕见疾病的早期描述。
In 1999, we reviewed the histopathological and immunological characteristics of eight dogs with this disease, and proposed the name exfoliative cutaneous lupus erythematosus (ECLE). Clinical, histopathological and immunological data from 25 dogs with ECLE were
later and described in more detail .
在1999年，我们回顾了八只患有此种疾病的犬的组织病理学和免疫学特征，并提出了表皮剥脱型皮肤红斑狼疮（ECLE）。临床上对25只患有表皮剥脱型皮肤红斑狼疮的犬的组织病理学和免疫学的数据进行了更详细的整理和描述。
Incidence and prevalence 发病率和流行率
At this time, there is insufficient information on canine ECLE to appropriately assess the incidence and prevalence of this disease in dogs. It appears to have a worldwide distribution.
目前，没有足够的关于犬表皮剥脱型皮肤红斑狼疮的信息来适当地评估这种疾病在犬中的发病率和流行率。全世界都有分布。
Signalment 特征
This variant of CCLE is predominantly seen in GSHPs.A large pedigree analysis of 235 purebred GSHPs and experimental mating studies established that this disease was transmitted on an autosomal recessive manner.A single nucleotide polymorphism on the CFA 18 chromosome was found to perfectly segregate with the trait in 267 dogs. Interestingly, ECLE has been diagnosed also in several Magyar viszlas living in western Europe;this observation is noteworthy, as viszlas share a common ancestry with GSHPs.
这种慢性皮肤红斑狼疮变异型主要见于德国短毛指示犬。对235只纯种德国短毛指示犬的血统分析和实验室交配研究证实了这种疾病是常染色体隐性遗传。在267只犬中发现CFA18染色体上的单核苷酸多态性与性状完全分离。有趣的是，生活在西欧的匈牙利维兹拉犬上也诊断出了表皮剥脱型皮肤红斑狼疮；这一点值得注意了，因为该犬和德国短毛指示犬有共同的祖先。
Adding the cases from the largest case series to those of the genome-wide association study yielded 45 GSHPs already reported with ECLE: there were 26 females and 19 males with a female-to-male ratio of 1.4. The first clinical signs usually occurred in juveniles or young adult dogs with a median age of onset of 8 months (range:7 weeks to 3.5 years).
将最大病例报告的病例进行全基因相关研究中，已报道出现45只患有表皮剥脱型皮肤红斑狼疮的德国短毛指示犬：其中26只雌性和19只雄性，雌雄比例是1.4。首次临床症状通常发生在青年或年轻成年犬上，中位发病年龄是8月龄（范围：7周龄至3.5岁）。
Clinical signs 临床症状
In the largest clinical case series of ECLE in GSHPs,the most prominent skin lesions were scaling and alopecia, which affected 25 (100%) and 19 (76%) of the reported dogs, respectively (Fig. 4a,b). Follicular casts were noted in one third of patients (Fig. 4a,b). Recently seen GSHPs with ECLE were found to also exhibit irregular and polycyclic patches and plaques with dyspigmentation and some scarring (personal observations; Fig. 4c,f). In this form of canine CCLE, skin lesions typically affect the muzzle, pinnae and dorsal trunk and then progress to involve the limbs,sternum and ventral abdomen. Generalized skin lesions are found in most dogs, while crusting, with or without an underlying ulceration, was recorded in one fourth of patients in the largest series of GSHPs. In one dog of that report, ulcers were so extensive that they resulted in bacterial septicemia. Mild pruritus was recorded in one third of GSHPs with ECLE.
在最大的德国短毛指示犬表皮剥脱型皮肤红斑狼疮病例系列中，最显著的皮肤病变是皮屑和脱毛，分别出现在22只（100%）和19只（76%）报道犬中（图4a、b）。三分之一的病患会出现毛囊管型（图4a、b）。最近发现的患有表皮剥脱型皮肤红斑狼疮的德国短毛指示犬也表现出不规则的和多环的斑片和斑块，并伴有色素沉着和一些瘢痕（个人观察；图4c、f）。在这种形式的犬慢性皮肤红斑狼疮中，皮肤病变通常出现在口鼻、耳廓和躯干背侧，然后逐步发展到四肢、胸廓和腹部腹侧。在大多数犬中通常发生一般的皮肤病变，而记录的最大的德国短毛指示犬病例系列中四分之一的犬出现了结痂、有或没有潜在溃疡。在该报道的一只犬中出现大范围的溃疡，导致了细菌性败血症。在记录的患有表皮剥脱型皮肤红斑狼疮的德国短毛指示犬病例报告中三分之一的犬出现了轻度瘙痒。
Overall, skin lesions of ECLE in viszla dogs are nearly identical to those seen in GSHPs with the same disease (Fig.5a-d). Furthermore, in some viszlas, the alopecic lesions are circumscribed and resemble those of the so-called “sebaceous adenitis of viszlas” (Fig, 5a,d). This observation, as well as the presence of typical histological changes of CLE in these dogs, raises the suspicion that some of the viszlas reported with sebaceous adenitis might have had, in fact, ECLE. In fact, in both GSHPs and Magyar viszlas, (granulomatous) sebaceous adenitis is the perfect mimic for ECLE.
总的来说，在维兹拉犬中表皮剥脱型皮肤红斑狼疮的皮肤病变几乎与德国短毛指示犬相同（图5a-d）。此外，在一些维兹拉犬中，脱毛的病变受到局限，类似于所谓的“维兹拉犬的皮脂腺炎”（图5a、d）。这一发现以及在这些犬中存在的典型的皮肤红斑狼疮的组织学变化，怀疑那些报道中患皮脂腺炎的维兹拉犬实际上是患了表皮剥脱型皮肤红斑狼疮。事实上，在德国短毛指示犬和匈牙利维兹拉犬中，（肉芽肿性）皮脂腺炎与表皮剥脱型皮肤红斑狼疮极为相似。
A generalized peripheral lymphadenomegaly was reported in one-third of GSHPs with ECLE; lymph node enlargement was also described in other reports. Many GSHPs with ECLE eventually develop signs suggestive of arthralgia, which manifests as a stiff gait, lameness or an arched back.In one report, all six dogs were infertile, with azoospermia and irregular or arrested cycles in females.
在患有表皮剥脱型皮肤红斑狼疮的德国短毛指示犬中，有三分之一出现全身性外周淋巴结肿大；在其他报道中也描述了淋巴结肿大。许多患有表皮剥脱型皮肤红斑狼疮的德国短毛指示犬最终会出现提示关节疼痛的症状，显著表现为僵硬的步态、跛行或拱背。在一篇报道中，所有六只犬都无生育能力，表现为无精症和雌性发情周期不规则或停滞。
Laboratory evaluation 实验室检查
While rare GSHPs with ECLE have mild anemia, fluctuating thrombocytopenia is seen more commonly in these dogs; serum biochemistry and urinalysis usually do not exhibit consistent changes, except for hyperglobulinemia seen occasionally.
虽然患有表皮剥脱型皮肤红斑狼疮的德国短毛指示犬罕见出现轻度贫血，但这些犬中常见的是波动性血小板减少；血清生化和尿检通常不表现出一致的变化，除了偶尔出现的高球蛋白血症。
Fine needle aspirate material from enlarged peripheral lymph nodes was submitted for cytological evaluation in one GSHP with lymphadenomegaly, and it revealed lymphoid hyperplasia. Spinal radiographs, myelogram and cerebrospinal fluid analysis and stifle and hock joint aspirates were performed in dogs suffering from intermittent arthralgia, but they failed to identify any underlying abnormality.
在一只淋巴结肿大的德国短毛指示犬中，在外周淋巴结肿大部位做细针抽吸进行细胞学检查，并显示了淋巴组织增生。对患有间歇性关节疼痛的犬进行脊柱X线片拍摄、脊髓造影和脑脊液分析和后膝关节以及肘关节抽吸，但未能发现任何潜在的异常。
Histopathology 组织病理学
The largest compilation of dogs with ECLE confirms previous information regarding the histopathology of this disease. In this study, microscopic examination revealed a cellrich interface dermatitis (Fig. 6a,b) characterized by moderate to marked dermal lymphocyte infiltrate that tended to be multifocal, rather than always organized into a subepidermal band. Typical of cell-rich interface lesions, the apoptosis of basal keratinocytes was accompanied by moderate to marked lymphocytic exocytosis in the lower epidermis (Fig. 6b). In addition, biopsies of most dogs had mild lymphocytic exocytosis and keratinocyte apoptosis in the upper epidermis. Diffuse orthokeratotic hyperkeratosis was a notable feature of most biopsies and was usually moderate (Fig. 6b).
最大的犬表皮剥脱型皮肤红斑狼疮病例系列证实了以前关于这种疾病的组织病理学信息。在本研究中，显微镜检查显示了一种富含细胞的界面性皮炎（图6a、b），其特征为中度至重度的淋巴细胞真皮浸润，往往呈现多灶性，并不总组织形成表皮下层带。典型的富含细胞的界面性病变，基底角质细胞凋亡伴有中度到重度的表皮下层淋巴细胞外排作用（图6b）。此外，大多数犬活检显示表皮上层淋巴细胞外排作用和角质细胞凋亡。弥漫性正角化性角化过度是大多数活检的一个显著特征，通常是中度的（图6b）。
In the study by Bryden and colleagues, a lymphocytic interface mural folliculitis was also present in the infundibulum in all dogs, for which biopsy sections captured the infundibula of follicles, and it extended to inferior follicular segments in 92% of dogs (Fig. 6c,d). Sebaceous glands were also affected. A periglandular lymphocytic infiltrate was present in 63% of dogs, sebaceous glands were absent in 50% of all biopsy sections evaluated, and 16% of dogs lacked sebaceous glands in all biopsies (Fig. 6c).These latter features can lead to confusion with (primary)sebaceous adenitis. Additionally, a lymphocytic apocrine gland infiltrate was observed in 46% of dogs .
在Bryden和他的同事的研究中，所有犬活检切片捕捉到的毛囊漏斗部也存在淋巴细胞界面性毛囊壁炎，92%的犬会延伸到毛囊下部（图6c，d）。皮脂腺也受到影响。63%的犬存在腺周淋巴细胞浸润，50%的活检切片中没有皮脂腺，16%的犬在所有活检中缺乏皮脂腺（图6c）。这之后的特征可能与（初级）皮脂腺炎混淆。此外，46%的犬存在淋巴细胞顶泌腺浸润。
Immunopathology 免疫病理学 Direct immunofluorescence In one study , direct immunofluorescence testing performed on paraffin-embedded sections revealed the presence of in situ deposition of IgG, IgM, IgA and C3 in the epidermal basement membrane of 100%, 47%, 11% and 5% of GSHPs, respectively. The multifocal or continuous fine deposition of IgG was recorded in 61%, 35% and 77% of skin biopsy sections, respectively. Interestingly, the follicular basement membrane deposition of IgG was found in 41% of tested biopsies. 直接免疫荧光法 在一项研究中，对石蜡包埋切片进行了直接免疫荧光检测显示分别有100%、47%、11%和5%的德国短毛指示犬表皮基底膜中存在lgG、lgM、lgA和C3的原位沉积。分别有61%、35%和77%的皮肤活检切片中显示了lgG的多灶性或连续性的细砂沉淀。有趣的是，在41%的活检中发现了lgG的毛囊基底膜沉淀。 Indirect immunofluorescence Indirect immunofluorescence testing on sections of normal canine haired and salt-split-skin revealed the existence of circulating antifollicular IgG antibodies in the serum of 57% of tested GSHPs with ECLE. In addition, anti-sebaceous gland IgG antibodies were also detected in these dogs. Circulating anti-epidermal basement membrane antibodies were not observed, however. In three studies, antinuclear antibody serology usually remained below positive thresholds in GSHPs with ECLE . 间接免疫荧光法 对正常犬的毛发和盐裂皮肤进行间接免疫荧光显示57%的患有表皮剥脱型皮肤红斑狼疮的德国短毛指示犬的血清中存在循环抗毛囊lgG抗体。此外，在这些犬中也检测到抗皮脂腺lgG抗体。然而没有发现循环抗表皮基底膜抗体。在这三项研究中，患有表皮剥脱型皮肤红斑狼疮的德国短毛指示犬的抗核抗体血清通常保持在阳性阈值以下。 Immunohistochemistry Immunohistochemical staining confirmed the predominance of CD3-bearing T lymphocytes in the lower epidermis, superficial dermis, in the infundibulum of hair follicles and around sweat glands. These CD3-positive T lymphocytes infiltrated sebaceous glands and their associated ducts in samples collected from two dogs. 免疫组化 免疫组化染色证实了在下表皮、真皮浅表、毛囊漏斗部和汗腺周围携带CD3的T淋巴细胞占主导。从两只犬中采集的样本中，这些CD3阳性的T淋巴细胞浸润皮脂腺及其相关的导管。 Treatment and outcome The review of published reports has yielded inconsistent information on the treatment and outcome of this disease. The early descriptions of ECLE suggested some benefit of dietary changes, supplementation with fatty acids, anti-seborrheic shampoos, antibiotics and/or oral retinoids.The most recent case series reported the limited efficacy of immune-modulating drugs prescribed either as single or combination therapy (e.g.tetracycline-niacinamide combinations, doxycycline, oral glucocorticoids, azathioprine, ciclosporin, leflunomide, or hydroxychloroquine). 治疗和预后 对于已发表报告的审查得出了关于这种疾病的治疗和预后不一致的信息。早期对表皮剥脱型皮肤红斑狼疮的描述表明了饮食的改变、脂肪酸的补充、抗脂溢性香波、抗生素和/或口服维A酸的一些好处。最近的病例报告报道了使用免疫调节药物进行单一或联合治疗（四环素-烟酰胺联合制剂、多西环素、口服糖皮质激素、硫唑嘌呤、环孢菌素、米氟米特或羟氯喹）的有限疗效。
Hydroxychloroquine, an first-line antimalarial drug used in human CCLE, appeared to slow down the clinical progression in some dogs with ECLE; in contrast, high-dose ciclosporin reportedly was not able to halt lesion worsening. As the response to immunomodulators is heterogeneous in human CCLE variants , the use of high-dose oral glucocorticoids and adjunctive immunosuppressive regimens need to be investigated on an individual patient basis.
一种用于人类慢性皮肤红斑狼疮的一线抗疟疾药物-羟氯喹，似乎减缓了一些患有表皮剥脱型皮肤红斑狼疮的犬的临床进展；相反，据报道高剂量的环孢菌素无法阻止病变恶化。由于人类慢性皮肤红斑狼疮的变异型对免疫调节剂的反应不一样，因此需要在单个病例上研究使用高剂量的口服糖皮质激素和辅助免疫抑制方案。
Taking into account all GSHPs with ECLE for which a long-term outcome has been reported,over half of dogs are eventually euthanized for their lack of disease response to therapy. This makes this CLE variaiant the most challenging to treat among all those of canine CCLE.
所有患有表皮剥脱型皮肤红斑狼疮的德国短毛指示犬都已报道了长期的诊疗结果，超过一半的犬最终因缺乏对治疗的反应而被安乐。这使得在所有犬慢性皮肤红斑狼疮中，表皮剥脱型皮肤红斑狼疮这种变异型在治疗上最具有挑战性。
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Fig. 4 Clinical characteristics of canine exfoliative cutaneous lupus erythematosus in German shorthaired pointers.
a, b: poor hair coat, scaling and follicular casts are visible from a distance.
c, d, e, f: irregular plaques with hyperpigmentation and scaling can be seen on closer examination- (d-f) courtesy of Petra Bizikova, NC State University
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Fig. 5 Clinical characteristics of canine exfoliative cutaneous lupus erythematosus in Magyar viszlas.
a, b: multifocal, often coalescing, patches of alopecia are noted from afar.
c, d: atrophic scars and follicular casts and large scales develop in alopecic areas
-courtesy of Émilie Vidémont,University of Lyon, France
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Fig. 6 Histopathology of canine exfoliative cutaneous lupus erythematosus.
a: cell-rich, lymphocytic interface dermatitis is present with a distinct band-like(lichenoid) dermal infiltrate of lymphocytes, plasma cells and a few histiocytes. 100X
(b): in an area of well-developed interface dermatitis,laminated,orthokeratotic hyperkeratosis (exfoliation) is present, which is typical of the disease. 200X.
c: lymphocytic interface folliculitis and mural folliculitis involve the infundibulum (upper-right) as well as the isthmus and inferior segments (lower-left) of hair follicles. Sebaceous glands are absent in this biopsy, as is reported in some cases. 200X
(d): lymphocytic interface folliculitis and mural folliculitis are present in the external root sheath of anagen hair follicles.Telogen hair follicles can also be affected (not shown). 200X
